Functionalization of Pyridinium Derivatives with 1,4-Dihydropyridines Enabled by Photoinduced Charge Transfer

Article abstract of DOI:10.1021/acs.orglett.0c03347

By exploiting electron donor-acceptor (EDA) complexes between 1,4-dihydropyridines and N-amidopyridinium salts under visible light irradiation, we discovered that photoinduced intermolecular charge transfer induces a single-electron transfer event without requiring a photocatalyst for the facile functionalization of pyridines. The generality of this method is amenable to various types of 1,4-dihydropyridines radical precursors to generate structurally different radicals such as alkyl, acyl, and carbamoyl radicals, ultimately providing facile access to synthetically valuable C4-functionalized pyridines. A broad range of functional groups are well accommodated under mild and metal-free conditions, and the synthetic utility of the present method is showcased by the late-stage functionalization of a variety of biologically relevant pyridine-based compounds, pharmaceuticals, and peptide feedstocks.

Full text of DOI:10.1021/acs.orglett.0c03347

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Letter
Functionalization of Pyridinium Derivatives with 1,4-
Dihydropyridines Enabled by Photoinduced Charge Transfer
Inwon Kim, Seongjin Park, and Sungwoo Hong*
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ABSTRACT: By exploiting electron donor−acceptor (EDA) complexes between
1,4-dihydropyridines and N-amidopyridinium salts under visible light irradiation,
we discovered that photoinduced intermolecular charge transfer induces a single-
electron transfer event without requiring a photocatalyst for the facile
functionalization of pyridines. The generality of this method is amenable to various
types of 1,4-dihydropyridines radical precursors to generate structurally different
radicals such as alkyl, acyl, and carbamoyl radicals, ultimately providing facile access
to synthetically valuable C4-functionalized pyridines. A broad range of functional
groups are well accommodated under mild and metal-free conditions, and the
synthetic utility of the present method is showcased by the late-stage
functionalization of a variety of biologically relevant pyridine-based compounds,
pharmaceuticals, and peptide feedstocks.
Scheme 1. C4-Selective Pyridine Functionalization with
Various 1,4-DHPs by an EDA Complex Activation Strategy
he pyridine scaffolds are core units of various pharma-
T
ceuticals, natural products, and agrochemicals.1 Accord-
ingly, various synthetic techniques, such as Minisci-type cross-
coupling reactions, have been developed to rapidly functionalize
the pyridine motifs. Despite the fascinating advances in the acid-
activated pyridine functionalizations, the reactions using
unblocked pyridines frequently resulted in mixtures of undesired
byproducts due to competitive overalkylation and poor site
selectivity.2 Recently, pyridinium salts have drawn much
attention in radical chemistry as versatile pyridine surrogates,
which offers direct access to monofunctionalized pyridine
derivatives.3 In particular, a high degree of regioselectivity can
be achieved by changing the energy levels of orbitals of pyridines
and the steric effects of the activators. In light of these benefits,
pyridinium salts have found widespread use in a number of
visible-light-mediated radical reactions, in which single-electron
transfer (SET) manifolds are required.4
Photochemical strategies involving charge transfer in photon-
absorbing electron donor−acceptor (EDA) complexes have
emerged as powerful tools to promote a wide range of radical-
based transformations that bypass the need for an external
photocatalyst.5 In such protocols, Aggarwal6a and Glorius6b
reported photoactive Katritzky pyridinium salt-based EDA
complexes with electron donors such as diborons, Hantzsch
esters, and indoles. The generated alkyl radicals subsequently
undergo a series of deaminative cross-coupling reactions with
high efficiency (Scheme 1a).6 In addition, the Lakhdar group
used amines as electron donors to the pyridinium salts for the
facile generation of reactive radicals via EDA complexes, which
undergo a hydrogen atom transfer (HAT) process.7a,b We
recently disclosed a photochemical cross-coupling between N-
amidopyridinium salts and alkyl bromides to yield various C4-
alkylated pyridines.7c Driven by the need for a unified reaction
system to install various functionalities including alkyl, acyl, and
Received: October 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03347
© XXXX American Chemical Society
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carbamoyl groups, we sought to explore novel reactivity by
exploiting new types of electron donors that enable the effective
installation of interesting feedstock functional groups into
pyridines in a controllable manner, thus providing a potential
opportunity to enable pyridine functionalization. The utilization
of naturally abundant aldehydes is an appealing method to
enable the direct conversion of readily available chemicals into
value-added products. 1,4-Dihydropyridines (DHPs) easily
prepared from aldehydes in a single step can undergo oxidative
fragmentation to afford a broad range of C-centered radicals,
such as alkyl, acyl, and carbamoyl radicals, which can engage in
cross-coupling reactions.8 Inspired by the aforementioned
studies on EDA-mediated cross-coupling reactions, we specu-
lated that the radical generated by the SET process could then
engage in cross-coupling reactions with N-amidopyridinium
salts (Scheme 1b), which would offer an opportunity for the
facile functionalization of pyridines via a productive radical chain
process. Herein, we report an efficient method for the C4-
selective functionalization of pyridines9 by leveraging EDA
complex activation between the N-amidopyridinium salts and
1,4-DHPs upon visible light irradiation. The generality of this
method is amenable to various types of alkyl, acyl, and
carbamoyl radicals derived from 1,4-DHPs to provide facile
access to synthetically challenging C4-functionalized pyridines
under metal-free and mild reaction conditions.
Table 1. Reactions between N-Amidopyridinium Salts and
1,4-DHPs
a
b
entry
variations from standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
none
76
66
67
65
trace
trace
68
0
MeCN instead of 1,2-DCE
DCM instead of 1,2-DCE
chloroform instead of 1,2-DCE
toluene instead of 1,2-DCE
THF instead of 1,2-DCE
green LED instead of blue LED
in dark
with TEMPO
0
a
Reaction conditions: 1a (0.1 mmol) and 2a (1.5 equiv) at rt under
b
light irradiation using a blue LED at rt for 16 h under N2. Yields were
determined by H NMR. TEMPO = 2,2,6,6-tetramethylpiperidine-1-
1
oxyl.
DHP 2a. The necessity of light for a successful reaction was
confirmed by the control experiment (entry 8).
With the operationally simple optimized conditions, the
generality of the current method was explored (Figure 1). First,
various pyridinium substrates bearing electron-deficient or
electron-donating substituted C2-aryl groups were alkylated to
provide desired products (3a−3c). A thienyl-substituted
substrate was compatible with the optimized reaction conditions
(3d). Unsubstituted and C3-substituted pyridinium salts were
also readily alkylated to afford the corresponding C4-alkylated
products 3f and 3g with complete regioselectivity. Likewise,
valuable bicyclic 3h and bipyridinium derivatives 3i could be
successfully synthesized. Encouraged by the success of the
pyridinium salts, we tested the reactivity of a quinoline
derivative. Pleasingly, the quinolinium salt could also be used
as an efficient electron acceptor in a productive EDA complex to
afford the desired product 3j. Next, we evaluated the scope of
1,4-DHP radical precursors to investigate the reactivity of
differently substituted alkyl radicals. This method worked well
with a series of amino acid-derived 1,4-DHPs, such as
phenylalanine, leucine, and proline, to deliver the desired
products 3k, 3l, 3m, and 3n, respectively. The alkyl radical,
having an internal alkene from melonal that is often used in the
perfume industry, provided desired product 3o. Cyclic alkyl
radicals were successfully coupled with pyridinium salts (3p, 3q,
and 3r). Notably, unprotected and protected hydroxyl groups
were intact in these reaction conditions (3s and 3t). In addition,
bromide was tolerable under the current conditions to provide
product 3u, thus allowing further modification. Sterically
hindered tert-butyl (3v) and benzyl radicals (3w) efficiently
engaged in the couplings. Next, we attempted to extend this
pyridine functionalization protocol to the C4-selective carba-
moylation and acylation of pyridine to further expand scope
generality. With respect to carbamoyl and acyl radicals, we were
pleased to observe that diverse 1,4-DHPs were successfully
employed as effective cross-coupling partners with 1 by using
our standard reaction conditions. For example, a series of
carbamoyl and acyl radicals efficiently participated in the
reaction with various N-amidopyridinium salts, affording
cross-coupled products (3x−3am). The reactions successfully
We first sought to confirm the postulated photochemically
active EDA complexes between pyridinium salts and 1,4-DHPs
(see Figure S9 in Supporting Information). A significant red shift
was observed when pyridinium salt 1a and 1,4-DHP 2a were
combined, revealing that the shift in absorption wavelength is
likely attributed to the association of these two species. Next, we
conducted computational simulation using time-dependent
density functional theory (TDDFT)10 and observed a calculated
peak at 437 nm. This predicted peak is composed of a charge
transfer excitation from the donor π orbital of the 1,4-DHPs to
the acceptor π* orbital of the pyridinium salt. After observing
the possibility of an EDA complex between pyridinium salts and
1,4-DHPs, we further investigated continuous variations of each
component by employing Job’s analysis using UV/vis
absorption measurements, suggesting that the donor−acceptor
complex consists of 1a and 2a in a 1:1 ratio. In addition, by NMR
1
analysis, we observed that the H NMR signal of 2a and 1a
shifted downfield and upfield, respectively. The above experi-
ments and observations demonstrated the formation of the EDA
complex between pyridinium salts and 1,4-DHPs.
After confirmation of the formation of the donor−acceptor
complex between N-amidopyridinium salts and 1,4-DHPs, our
optimization began by monitoring the reactivity of pyridinium
salt 1a with DHP 2a under blue LED irradiation, as summarized
in Table 1. After screening key parameters, we observed that the
desired product 3a was formed in a 1,2-DCE solvent system at
room temperature in 76% yield without the need for an external
photocatalyst or additives (entry 1). Among the various solvent
systems, 1,2-DCE was determined to be the best, and other
solvents showed slightly diminished yields (entries 2−4). Not
surprisingly, toluene and THF did not lead to any conversion
because of poor pyridinium salt solubility (entries 5 and 6). It
should be noted that a comparable product yield was obtained at
a longer wavelength (approximately 525 nm) under green LED
irradiation, further supporting the formation of the EDA
complex in this reaction system (entry 7), considering the
shorter wavelength absorption of each pyridinium salt 1a and
B
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Figure 1. Substrate scope of the functionalization of pyridines. Reaction conditions: 1 (0.1 mmol) and 2 (0.15 mmol) at rt under light irradiation using
a blue LED for 16−24 h under N2. Yields of isolated products.
proceeded with the proline- and phenylalanine-derived DHPs to
yield desired products 3ai and 3aj.
Encouraged by the results that take place under extremely
mild reaction conditions, this method was next employed for the
C
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Figure 2. Free-energy profile and proposed reaction mechanism pathway of the para-functionalization of 1a. (a) Related free-energy profile. (b)
Proposed reaction pathway.
late-stage functionalization. To our delight, structurally complex
pyridine-based pharmaceutical compounds can be successfully
functionalized or prepared with this protocol. Of note, we
observed that a diverse range of functional groups were well
tolerated, including synthetically important chloro, fluoro,
acetate, ether, acetal, ester, amide, sulfonyl, internal alkene,
phenoxy, and thienyl groups. Specifically, vismodegib and
bisacodyl could be quickly modified with 1,4-DHPs (3an−
3aq), allowing the generation of new drug derivatives.
Additionally, this protocol can be used for the incorporation
of pyridines or quinolines into pharmaceuticals such as
galactopyranose, duloxetine, paroxetine, mexiletine, L-DOPA,
troxipide, and Tamiflu to deliver the corresponding products
(3ar−3ax) with excellent regioselectivity. Late-stage modifica-
tions of peptides have been drawing attention for drug
discovery,11 and this robust method was successfully applied
to tetra-peptide as exemplified by 3ay (Phe-Ala-Leu-Gly).
After demonstrating general applicability to a wide range of
scope, several control experiments were conducted to gain
insight into the mechanistic pathway. The formation of the
desired product was suppressed with TEMPO, and a significant
amount of alkyl radical-trapped adduct 4 was isolated (Scheme
S3). To determine whether the pyridines generated by
intermolecular charge transfer could act as coupling substrates,
crossover experiments were conducted with a mixture of
pyridinium salt 1a and pyridines. As expected, the reaction
took place at the C4 position of the pyridinium salt, producing
3a (Scheme S4).
transfer events of the 1,4-DHPs to 1a, various alkyl, acyl, or
carbamoyl radicals can be generated. Based on the computed
energy profile, the intermolecular radical addition to pyridinium
salt 1a determines the regioselectivity, resulting in the formation
of two possible regioisomers (C2 vs C4). Consistent with the
experimental observations, our calculations show that the
transition state TS-E C4-addition leading to the intermediate
E is 2.8 kcal/mol lower in energy than the C2-addition transition
state TS-E′. Next, subsequent deprotonation of the cationic
radical complex E and cleavage of the N−N bond ultimately
delivers the para-functionalized pyridine. In the process, the
extruded amidyl radical is reduced by 1,4-DHP to yield a new
radical species and initiate a radical chain pathway, which is
supported by the measured high reaction quantum yield (Φ =
16.0).12 The resulting amidyl radical also acts as a base in the
deprotonation step to produce the desired product. Taken
together, the amido group at the pyridinium salt plays multiple
roles as a radical chain propagator, base, and regioselectivity
inducer.
In summary, we have developed efficient and catalyst-free
pyridine functionalization enabled by the unexplored EDA
complex between N-amidopyridinium salts and 1,4-DHPs under
visible-light promoted conditions. The generality of this
transformation was demonstrated through reactions with
various types of alkyl, acyl, and carbamoyl radicals to ultimately
yield synthetically valuable C4-functionalized pyridines with
excellent regiocontrol, thereby expanding the chemical space of
privileged pyridine scaffolds under extremely mild and metal-
free conditions. The synthetic utility of this method was
illustrated by the late-stage modification of a variety of
biologically relevant compounds with broad functional group
tolerance, which would otherwise be difficult to access.
With the experimentally observed excellent regioselectivities,
we carried out density functional theory (DFT) calculations of
alkylation to elucidate the reaction mechanism and regiochem-
ical outcomes (Figure 2a). The reaction is initiated by the
formation of an EDA complex from pyridinium salt 1a and 1,4-
DHP upon irradiation with visible light. Single-electron
oxidation of 1,4-DHP by 1a generates radical cation A, which
produces alkyl radical C with a barrier of 2.2 kcal/mol. As shown
in Figure 1b, after photoinduced intermolecular electron
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03347.
D
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2019, 21, 2082. (p) Bao, X.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed.
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(r) Lee, K.; Lee, S.; Kim, N.; Kim, S.; Hong, S. Angew. Chem., Int. Ed.
Experimental procedures and characterization of new
compounds (1H and 13C NMR spectra) (PDF)
AUTHOR INFORMATION
́
2020, 59, 13379. (s) Inial, A.; Morlet-Savary, F.; Lalevee, J.; Gaumont,
■
A.-C.; Lakhdar, S. Org. Lett. 2020, 22, 4404. (t) Rammal, F.; Gao, D.;
Boujnah, S.; Gaumont, A.-C.; Hussein, A. A.; Lakhdar, S. Org. Lett.
2020, 22, 7671.
Corresponding Author
Sungwoo Hong − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Korea; Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon 34141,
Korea; orcid.org/0000-0001-9371-1730;
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A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2019, 58, 5697. (e) Wang, C.;
Qi, R.; Xue, H.; Shen, Y.; Chang, M.; Chen, Y.; Wang, R.; Xu, Z. Angew.
Chem., Int. Ed. 2020, 59, 7461. For selected examples not using EDA
complexes with Katritzky salts, see: (f) Liao, J.; Guan, W.; Boscoe, B. P.;
Tucker, J. W.; Tomlin, J. W.; Garnsey, M. R.; Watson, M. P. Org. Lett.
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Molander, G. A. Org. Lett. 2019, 21, 3346. (h) Martin-Montero, R.;
Yatham, V. R.; Yin, H.; Davies, J.; Martin, R. Org. Lett. 2019, 21, 2947.
(i) Kim, I.; Im, H.; Lee, H.; Hong, S. Chem. Sci. 2020, 11, 3192.
Email: hongorg@kaist.ac.kr
Authors
Inwon Kim − Department of Chemistry, Korea Advanced Institute
of Science and Technology (KAIST), Daejeon 34141, Korea;
Center for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science (IBS), Daejeon 34141, Korea
Seongjin Park − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon 34141,
Korea; Center for Catalytic Hydrocarbon Functionalizations,
Institute for Basic Science (IBS), Daejeon 34141, Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03347
́
(7) (a) Quint, V.; Morlet-Savary, F.; Lohier, J. F.; Lalevee, J.;
Gaumont, A.-C.; Lakhdar, S. J. Am. Chem. Soc. 2016, 138, 7436.
Notes
̀
́
(b) Quint, V.; Chouchene, N.; Askri, M.; Lalevee, J.; Gaumont, A.-C.;
Lakhdar, S. Org. Chem. Front. 2019, 6, 41. (c) Jung, S.; Shin, S.; Park, S.;
Hong, S. J. Am. Chem. Soc. 2020, 142, 11370.
(8) For selected reviews, see: (a) Huang, W.; Cheng, X. Synlett 2017,
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2019, 17, 6936. For selected examples of alkyl radicals from 1,4-DHPs,
see: (c) Gutierrez-Bonet, A.; Tellis, J. C.; Matsui, J. K.; Vara, B. A.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported financially by the Institute for Basic
Science (IBS-R010-A2).
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