Visible-Light-Mediated C-H Alkylation of Pyridine Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c02863

We report herein a visible-light-mediated C-H alkylation of pyridine derivatives that proceeds by simple combination of a large variety of N-alkoxypyridinium ions with alkanes in the presence of 2 mol % of fac-Ir(ppy)3 under blue illumination. The mild reaction conditions together with the high group functional tolerance make of this process a useful synthetic platform for the construction of structurally strained heterocycles. Detailed mechanistic investigations, including density functional theory calculations and quantum yield measurement, allowed us to understand factors controlling the reactivity and the selectivity of the reaction.

Full text of DOI:10.1021/acs.orglett.0c02863

pubs.acs.org/OrgLett
Letter
Visible-Light-Mediated C−H Alkylation of Pyridine Derivatives
Fatima Rammal, Di Gao, Sondes Boujnah, Annie−Claude Gaumont, Aqeel A. Hussein,
and Sami Lakhdar*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02863
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report herein a visible-light-mediated C−H alkylation of pyridine derivatives that proceeds by simple
combination of a large variety of N-alkoxypyridinium ions with alkanes in the presence of 2 mol % of fac-Ir(ppy)3 under blue
illumination. The mild reaction conditions together with the high group functional tolerance make of this process a useful synthetic
platform for the construction of structurally strained heterocycles. Detailed mechanistic investigations, including density functional
theory calculations and quantum yield measurement, allowed us to understand factors controlling the reactivity and the selectivity of
the reaction.
Scheme 1. (A) Reported Approaches for C−H Alkylation of
lkylated heteroarenes are ubiquitous chemical motifs
Apresent in pharmaceuticals, natural products, and ligand
scaffolds.1,2 While access to such molecules can be achieved
with different synthetic methodologies, the oxidative cross-
coupling between two C−H compounds is evidently one of the
most elegant approaches as it provides a direct construction of
the C−C bond in a step- and atom-economical fashion.3−7 For
instance, the generation of an alkyl radical through a hydrogen
atom transfer (HAT) event and its subsequent addition to a
heteroarene ring followed by a formal hydrogen atom loss can
provide a rapid and direct method for heterocycle C−H
alkylation (Scheme 1). This approach, known as the Minisci
reaction,8−11 gained much attention during the past decade
with the spectacular renaissance of the field of photoredox
catalysis that provides very mild conditions for the generation
of alkyl radicals.12−19 While various elegant photoredox
Minisci reactions employing a HAT strategy for the generation
of the alkyl radical have been developed, there is in most cases
a need to use an external oxidant and stoichiometric amounts
of Brønsted acids to activate the heteroarene ring toward
radical addition.20−27
a
Heteroarenes. (B) Current Work
a
HAT denotes hydrogen atom transfer.
On the basis of their abilities to generate strong hydrogen
atom abstractors (alkoxy radicals) under visible-light photo-
catalytic conditions,28,29 as well as their high electrophilicity,
N-alkoxypyridinium ions (NAPs) are unique scaffolds to
achieve a photocatalytic Minisci reaction. This approach has
nicely been demonstrated by the Hong group in a certain
number of examples, including acylation and intramolecular
alkylations.30−34 However, the direct association of NAPs with
Received: August 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02863
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
alkanes to achieve Minisci reaction has not been reported so
far. Furthermore, it is well-known that pyridines are less
reactive than quinolines and isoquinolines in various Minisci
reactions.35−37 We therefore decided to investigate the
reactions of NAPs with alkanes under mild photoredox
conditions.
We initially explored the reaction conditions by investigating
the effect of the photocatalyst, solvent, and the base through
the reaction of the N-methoxypyridinium (1a) with 2a. As
shown in Table 1, fac-Ir(ppy)3 gave excellent conversion of 3a
product was observed. Finally, 33% of 3a was observed when
the base was not employed under the optimized conditions
(entry 16). The result might be attributed to the pyridinium
counterion that played the role of the base in the process.
Next, we set out to investigate the scope of this visible-light
C−H alkylation of heteroarenes with alkanes (Figure 1). The
reaction of cyclohexane (2a) with 4-substituted N-alkoxypyr-
idinium ions proceeded smoothly, giving the 2-alkylated
Table 1. Optimization of the Photocatalytic Alkylation
Reaction between the N-Alkoxypyridinium 1a and
a
Cyclohexane 2a
a
b
entry
photocatalyst (PC)
base
solvent
3a, yield (%)
1
2
3
4
5
6
7
8
Ru(bpy)3
Eosin Y
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
MeCN
MeCN
MeCN
MeCN
THF
traces
traces
64
Hong’s PC
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
95
traces
traces
traces
traces
traces
traces
30
55
41
traces
0
33
DMF
DCM
AcOEt
DMSO
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
15
16
K2HPO4
K2CO3
NaHCO3
NaHCO3
c
fac-Ir(ppy)3
fac-Ir(ppy)3
a
Reaction conditions: N-methoxy-4-methylpyridinium methyl sulfate
1a (0.21 mmol, 1 equiv), cyclohexane 2a (1.1 mmol, 5 equiv), solvent
b
(4.2 mL), blue LEDs (5W), 1 h. NMR yields are determined from
1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as internal
c
standard. Reaction performed in the dark.
(Table 1, entry 4, 95%) when 5 equiv of 2a were mixed with 1a
in the presence of NaHCO3 as a base in acetonitrile under blue
light irradiation. While good conversion was obtained with the
3-phosphonated quinolinone (entry 3, 64%), known as the
Hong photocatalyst, under the same conditions as with fac-
Ir(ppy)3, only traces of 3a were observed with Ru(bpy)3 and
eosin Y (entries 1 and 2). A solvent screening, including THF,
DMF, DCM, AcOEt, DMSO, and CH3Cl (entries 5−10),
revealed no formation of the desired adduct. We next studied
the effect of the base on the reaction and found modest
conversion (30−55%) with the inorganic bases Na2CO3 (entry
11), K2HPO4 (entry 12), and K2CO3 (entry 13). The absence
of photocatalyst (entry 14) and the visible-light irradiation
(entry 15) were detrimental for the C−H alkylation as no
Figure 1. Photocatalytic C−H alkylation of heteroarenes. Reaction
conditions: N-alkoxypyridinium methylsulfate 1 (1 equiv), 2a (5
equiv), fac-Ir(ppy)3 (2 mol %), NaHCO3 (1.2 equiv) CH3CN (0.05
M), blue LEDs (5W), 1 h.
B
https://dx.doi.org/10.1021/acs.orglett.0c02863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
pyridines (3a−3f) in 50−99% yields. Remarkably, the reaction
works well with both electron-donating or electron-with-
drawing groups, tolerating cyano (3c), trifluoromethyl (3d),
and carbonyl (3e) groups.
intermediate (Int2). The radical addition at the C2 position
proceeds with an activation energy of 14.8 kcal/mol. This weak
difference between both attacks, i.e. at C2 and C4 position,
may rationalize the low regioselectivity observed. Next, a fast
deprotonation of Int2 by a base gives the Int3 that upon N−O
bond cleavage forms the final product 3 and release the
methoxyl radical to start a new reaction cycle. This radical
chain pathway explains the high measured quantum yield of
the reaction Φ = 62.9 (see the Supporting Information for
details). The calculated mechanism is in good agreement with
the experimental reaction time.
Although visible-light-mediated alkylation of heteroarenes
has been widely reported during the past few years, the
reaction scope has mainly been restricted to isoquinolines and
quinolines. In this study, we showed that alkylation of
pyridines can also be achieved efficiently by simply combining
N-methoxylpyridinium ions with alkanes in the presence of low
loading (2 mol %) of the readily accessible fac-Ir(ppy)3 under
blue light illumination. The broad scope and functional group
tolerance are excellent features of this method. The detailed
experimental and computational mechanistic studies con-
ducted in this study are not only allowed understanding
factors controlling this photoalkylation reaction but will also
help the design of new visible-light-induced C−H functional-
ization of heteroarenes.
The reaction works equally well with 2-substituted
pyridiniums. Both regioisomers, C2- and C4-alkylated
pyridines (3g−3j), were obtained in equal proportions (1:1
ratio), except in the case of 2-benzylpyridinium ion where the
C2 adduct was obtained as a major regioisomer (C2:C4 = 4:1).
The reaction is not only restricted to pyridines as alkylated
quinolines (3k−3n), 2,2-quinoline (3o), and phenanthridine
(3p) were obtained in good to excellent yields (Figure 1).
We further extended the scope of the photocatalytic
approach to cycloheptane (2b) and cyclopentane (2c) (Figure
2). Remarkably, a large variety of heteroarylated alkanes (3q−
3zb) were isolated in yields from 34 to 99%. Here again, the
reaction is compatible with quinolines derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02863.
Quantum yield measurement, DFT calculations, exper-
imental procedures, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
́
Sami Lakhdar − Universite Paul Sabatier, Laboratoire
́
́
́
Heterochimie Fondamentale et Appliquee, Toulouse 31062
Cedex 09, France; orcid.org/0000-0002-1168-7472;
Email: lakhdar@chimie.ups-tlse.fr
Authors
Fatima Rammal − Normandie Univ, LCMT, ENSICAEN,
UNICAEN, CNRS, Caen 14000, France
Di Gao − Normandie Univ, LCMT, ENSICAEN, UNICAEN,
CNRS, Caen 14000, France
Sondes Boujnah − Normandie Univ, LCMT, ENSICAEN,
UNICAEN, CNRS, Caen 14000, France
Annie−Claude Gaumont − Normandie Univ, LCMT,
ENSICAEN, UNICAEN, CNRS, Caen 14000, France
Aqeel A. Hussein − College of Dentistry, University of Al-
Ameed, Karbala, Iraq
Figure 2. Free energy profile for the photoinitiated C−C bond
formation in the reaction of pyridinium ion and cyclohexane.
Calculations were performed at the SMD-(ACN)-M06-2X/def2-
TZVP//B3LYP/6-31+G(d) level of theory. Energies in parentheses
are reported for addition at the C2 position. See the Supporting
Information for computational details.
The reaction mechanism of the visible-light-mediated
alkylation of heteroarenes is depicted in Figure 2. It starts
with the generation of the methoxyl radical through single-
electron reduction of the N−alkoxpyridinium ion by the
excited state of the photocatalyst (PC*). This event is
thermodynamically viable, and we have previously demon-
strated the generation of (MeO•) by EPR spectroscopy.38−41
DFT calculations show plausible HAT between the methoxyl
radical and cyclohexane (2a) to form the cyclohexyl radical
(Int 1). The latter reacts at the C4 of the pyridinium ion (1)
position (ΔG⧧ = 14.4 kcal/mol) to form the radical
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02863
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the CNRS, Normandie Universite, Labex
Synorg (ANR-11-LABX-0029), for financial support. F.R. is
■
́
C
https://dx.doi.org/10.1021/acs.orglett.0c02863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Secondary Amines: Remarkable Selectivity of Azetidines. Org. Lett.
2018, 20 (19), 6003−6006.
indebted to the French Ministry of Research for a doctoral
fellowship. The authors acknowledge the computational
resources from iridis4 supercomputers supported by the
University of Southampton. The authors thank Ms. Alya
Inial for her help with the preparation of compound 3a.
(21) Li, G. X.; Hu, X.; He, G.; Chen, G. Photoredox-Mediated
Minisci-Type Alkylation of N-Heteroarenes with Alkanes with High
Methylene Selectivity. ACS Catal. 2018, 8 (12), 11847−11853.
(22) Dong, J.; Xia, Q.; Lv, X.; Yan, C.; Song, H.; Liu, Y.; Wang, Q.
Photoredox-Mediated Direct Cross-Dehydrogenative Coupling of
Heteroarenes and Amines. Org. Lett. 2018, 20 (18), 5661−5665.
(23) Grainger, R.; Heightman, T. D.; Ley, S. V.; Lima, F.; Johnson,
C. N. Enabling Synthesis in Fragment-Based Drug Discovery by
Reactivity Mapping: Photoredox-Mediated Cross-Dehydrogenative
Heteroarylation of Cyclic Amines. Chem. Sci. 2019, 10 (8), 2264−
2271.
DEDICATION
■
This work is dedicated to Prof. Pierre H. Dixneuf (University
of Rennes) for his excellent contribution to organometallic
chemistry and catalysis.
REFERENCES
■
(24) Devari, S.; Shah, B. A. Visible Light-Promoted C-H
Functionalization of Ethers and Electron-Deficient Arenes. Chem.
Commun. 2016, 52 (7), 1490−1493.
(25) Jin, J.; MacMillan, D. W. C. Direct α-Arylation of Ethers
through the Combination of Photoredox-Mediated C-H Functional-
ization and the Minisci Reaction. Angew. Chem., Int. Ed. 2015, 54 (5),
1565−1569.
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57 (24), 10257−10274.
(2) Baumann, M.; Baxendale, I. R. An Overview of the Synthetic
Routes to the Best Selling Drugs Containing 6-Membered Hetero-
cycles. Beilstein J. Org. Chem. 2013, 9, 2265−2319.
(26) Quattrini, M. C.; Fujii, S.; Yamada, K.; Fukuyama, T.; Ravelli,
D.; Fagnoni, M.; Ryu, I. Versatile Cross-Dehydrogenative Coupling of
Heteroaromatics and Hydrogen Donors via Decatungstate Photo-
catalysis. Chem. Commun. 2017, 53 (15), 2335−2338.
(27) Okugawa, N.; Moriyama, K.; Togo, H. Introduction of Ether
Groups onto Electron-Deficient Nitrogen-Containing Heteroaro-
matics Using Radical Chemistry under Transition-Metal-Free
Conditions. Eur. J. Org. Chem. 2015, 2015 (22), 4973−4981.
(28) He, F. S.; Ye, S.; Wu, J. Recent Advances in Pyridinium Salts as
Radical Reservoirs in Organic Synthesis. ACS Catal. 2019, 9 (10),
8943−8960.
(3) Chen, X.; Engle, K. M.; Wang, D. H.; Jin-Quan, Y.
Palladium(II)-CataIyzed C-H Aetivation/C-C Cross-Coupling Re-
actions: Versatility and Practicality. Angew. Chem., Int. Ed. 2009, 48
(28), 5094−5115.
(4) Rouquet, G.; Chatani, N. Catalytic Functionalization of C(sp2)-
H and C(sp3)-H Bonds by Using Bidentate Directing Groups. Angew.
Chem., Int. Ed. 2013, 52 (45), 11726−11743.
(5) Park, S. J.; Price, J. R.; Todd, M. H. Oxidative Arylation of
Isochroman. J. Org. Chem. 2012, 77 (2), 949−955.
(6) Matcha, K.; Antonchick, A. P. Metal-Free Cross-Dehydrogen-
ative Coupling of Heterocycles with Aldehydes. Angew. Chem., Int. Ed.
2013, 52 (7), 2082−2086.
̈
(29) Rossler, S. L.; Jelier, B. J.; Magnier, E.; Dagousset, G.; Carreira,
E. M.; Togni, A. Pyridinium Salts as Redox-Active Functional Group
Transfer Reagents. Angew. Chem., Int. Ed. 2020, 59 (24), 9264−9280.
(30) Kim, I.; Kang, G.; Lee, K.; Park, B.; Kang, D.; Jung, H.; He, Y.
T.; Baik, M. H.; Hong, S. Site-Selective Functionalization of
Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with
Quinolinone. J. Am. Chem. Soc. 2019, 141 (23), 9239−9248.
(31) Jeon, J.; He, Y. T.; Shin, S.; Hong, S. Visible-Light-Induced
Ortho-Selective Migration on Pyridyl Ring: Trifluoromethylative
Pyridylation of Unactivated Alkenes. Angew. Chem., Int. Ed. 2020, 59
(1), 281−285.
(7) Liu, D.; Liu, C.; Lei, A. Copper-Catalysed Oxidative C−H/C−H
Coupling between Olefins and Simple Ethers. Chem. Commun. 2014,
50 (28), 3623−3626.
(8) Proctor, R. S. J.; Phipps, R. J. Recent Advances in Minisci-Type
Reactions. Angew. Chem., Int. Ed. 2019, 58 (39), 13666−13699.
(9) Caronna, T.; Gardini, G. P.; Minisci, F. Nucleophilic Character
of Acyl Radicals: A New Selective Type of Aromatic Acylation. J.
Chem. Soc. D 1969, 201 (5), 201.
(10) Minisci, F.; Vismara, E.; Fontana, F. Recent Developments of
Free-Radical Substitutions of Heteroaromatic Bases. Heterocycles
1989, 28 (1), 489−519.
(11) Minisci, F.; Bertini, F.; Galli, R.; Perchinijmmo, M. Character of
Alkyl. Tetrahedron 1971, 27, 3575.
(32) Jung, S.; Lee, H.; Moon, Y.; Jung, H. Y.; Hong, S. Site-Selective
c-h Acylation of Pyridinium Derivatives by Photoredox Catalysis. ACS
Catal. 2019, 9 (11), 9891−9896.
(33) Kim, I.; Park, B.; Kang, G.; Kim, J.; Jung, H.; Lee, H.; Baik, M.
H.; Hong, S. Visible-Light-Induced Pyridylation of Remote C(sp3)−
H Bonds by Radical Translocation of N-Alkoxypyridinium Salts.
Angew. Chem., Int. Ed. 2018, 57 (47), 15517−15522.
(34) Kim, Y.; Lee, K.; Mathi, G. R.; Kim, I.; Hong, S. Visible-Light-
Induced Cascade Radical Ring-Closure and Pyridylation for the
Synthesis of Tetrahydrofurans. Green Chem. 2019, 21 (8), 2082−
2087.
(12) Xuan, J.; Xiao, W. J. Visible-Light Photoredox Catalysis. Angew.
Chem., Int. Ed. 2012, 51 (28), 6828−6838.
̈
(13) Marzo, L.; Pagire, S. K.; Reiser, O.; Konig, B. Visible-Light
Photocatalysis: Does It Make a Difference in Organic Synthesis?
Angew. Chem., Int. Ed. 2018, 57 (32), 10034−10072.
(14) Yoon, T. P.; Ischay, M. A.; Du, J. Visible Light Photocatalysis as
a Greener Approach to Photochemical Synthesis. Nat. Chem. 2010, 2
(7), 527−532.
(35) Liang, X. A.; Niu, L.; Wang, S.; Liu, J.; Lei, A. Visible-Light-
Induced C(sp 3)-H Oxidative Arylation with Heteroarenes. Org. Lett.
2019, 21 (7), 2441−2444.
̈
(15) Wimmer, A.; Konig, B. Photocatalytic Formation of Carbon-
Sulfur Bonds. Beilstein J. Org. Chem. 2018, 14, 54−83. See Scheme 1.
(16) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116 (17), 10075−10166.
(36) Niu, L.; Liu, J.; Liang, X. A.; Wang, S.; Lei, A. Visible Light-
Induced Direct α C−H Functionalization of Alcohols. Nat. Commun.
2019, 10 (1), 1−7.
(17) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113 (7), 5322−5363.
(18) Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light
Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc.
Rev. 2011, 40 (1), 102−113.
(37) Bieszczad, B.; Perego, L. A.; Melchiorre, P. Photochemical C−
H Hydroxyalkylation of Quinolines and Isoquinolines. Angew. Chem.,
Int. Ed. 2019, 58 (47), 16878−16883.
́
(38) Quint, V.; Morlet-Savary, F.; Lohier, J. F.; Lalevee, J.; Gaumont,
A. C.; Lakhdar, S. Metal-Free, Visible Light-Photocatalyzed Synthesis
of Benzo[b]Phosphole Oxides: Synthetic and Mechanistic Inves-
tigations. J. Am. Chem. Soc. 2016, 138 (23), 7436−7441.
́
(19) Wang, C. S.; Dixneuf, P. H.; Soule, J. F. Photoredox Catalysis
for Building C-C Bonds from C(Sp2)-H Bonds. Chem. Rev. 2018, 118
(16), 7532−7585.
́
(39) Inial, A.; Morlet-Savary, F.; Lalevee, J.; Gaumont, A. C.;
(20) Bosset, C.; Beucher, H.; Bretel, G.; Pasquier, E.; Queguiner, L.;
Henry, C.; Vos, A.; Edwards, J. P.; Meerpoel, L.; Berthelot, D.
Minisci-Photoredox-Mediated α-Heteroarylation of N-Protected
Lakhdar, S. Visible-Light-Mediated Access to Phosphate Esters. Org.
Lett. 2020, 22 (11), 4404−4407.
D
https://dx.doi.org/10.1021/acs.orglett.0c02863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
̀
́
(40) Quint, V.; Chouchene, N.; Askri, M.; Lalevee, J.; Gaumont, A.
C.; Lakhdar, S. Visible-Light-Mediated α-Phosphorylation of: N -Aryl
Tertiary Amines through the Formation of Electron-Donor-Acceptor
Complexes: Synthetic and Mechanistic Studies. Org. Chem. Front.
2019, 6 (1), 41−44.
̈
(41) Quint, V.; Noel-Duchesneau, L.; Lagadic, E.; Morlet-Savary, F.;
Lalevee, J.; Gaumont, A.-C.; Lakhdar, S. Metal-Free Generation of
Phosphorus-Centered Radicals for the Synthesis of Phosphorus-Based
́
Heterocycles: A Personal Account. Synthesis 2017, 49 (15), 3444.
E
https://dx.doi.org/10.1021/acs.orglett.0c02863
Org. Lett. XXXX, XXX, XXX−XXX