Photochemical C-H Silylation and Hydroxymethylation of Pyridines and Related Structures: Synthetic Scope and Mechanisms

Article abstract of DOI:10.1021/acscatal.0c03726

Considering the synthetic relevance of heteroarenes in various areas ranging from organic synthesis to medicinal chemistry, developing practically simple methodologies to access functionalized heteroarenes is of a significant value. Described herein is an efficient approach for C-H silylation and hydroxymethylation of pyridines and related heterocycles by the combination of silanes or methanol with readily available N-methoxypyridinium ions with a low catalyst loading (2 mol %) under blue light irradiation. The synthetic importance of the developed reactions is demonstrated by the synthesis of biologically relevant compounds. Electron paramagnetic resonance spectroscopy, quantum yield measurements, and density-functional theory calculations allowed us to understand reaction mechanisms of both photocatalytic reactions.

Full text of DOI:10.1021/acscatal.0c03726

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Research Article
Photochemical C−H Silylation and Hydroxymethylation of Pyridines
and Related Structures: Synthetic Scope and Mechanisms
́
Fatima Rammal, Di Gao, Sondes Boujnah, Aqeel A. Hussein, Jacques Lalevee, Annie-Claude Gaumont,
Fabrice Morlet-Savary, and Sami Lakhdar*
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ABSTRACT: Considering the synthetic relevance of heteroarenes in
various areas ranging from organic synthesis to medicinal chemistry,
developing practically simple methodologies to access functionalized
heteroarenes is of a significant value. Described herein is an efficient
approach for C−H silylation and hydroxymethylation of pyridines and
related heterocycles by the combination of silanes or methanol with
readily available N-methoxypyridinium ions with a low catalyst loading
(2 mol %) under blue light irradiation. The synthetic importance of the
developed reactions is demonstrated by the synthesis of biologically
relevant compounds. Electron paramagnetic resonance spectroscopy,
quantum yield measurements, and density-functional theory calcu-
lations allowed us to understand reaction mechanisms of both
photocatalytic reactions.
KEYWORDS: hydroxymethylation, mechanism, photoredox catalysis, pyridines, silylation
overcome by Wang, Zhang and co-workers,34 who disclosed a
visible light-mediated C−H silylation of heteroarenes by
employing trialkylhydrosilanes as silyl radical precursors
(Scheme 1). However, the protocol still requires over
stoichiometric amounts of peroxides and is restricted to five
pyridine structures. Likewise, the radical C−H hydroxymethy-
lation of heteroarenes has not been extensively developed since
the seminal report by Minisci,35−38 where heterocyclic bases
are combined with methanol and an oxidant (ammonium
persulfate) under strong acidic conditions.35 A milder version
of this photochemical process was recently disclosed by
DiRocco, Krska and co-workers by using [Ir(dF-CF3-
ppy)2(dtbpy)]PF6 as the photocatalyst and benzoyl peroxide
as the terminal oxidant.39
Based on the dual reactivity of N-alkoxypyridinium ions
(NAPs),40−45 as alkoxy radical precursors that are good
hydrogen abstractors46−48 and as electrophilic partners in
Minisci reactions, as previously reported by Hong and co-
workers,49−56 we hypothesized that NAPs should be a good
partner with silanes or methanol to accomplish photocatalytic
INTRODUCTION
■
Heteroaromatic moieties are among the most widespread
constituents of pharmaceutical compounds. Accordingly, the
introduction of new functionalities through C−H functional-
ization has attracted much interest during the last decades and
resulted in the development of several elegant stoichiometric
and catalytic strategies.1,2 Although transition metal-catalyzed
approaches are classically employed, the use of the well-known
Minisci reaction remained one of the most useful technolo-
gies.3 This reaction has recently gained remarkable interest
with the significant development of photoredox catalysis4−10
that, in contrast to classical methods (stoichiometric silver
oxidants at elevated temperatures), provided mild conditions
for the formation of radicals. Naturally, many elegant
photochemical Minisci-type reactions have been achieved
and have been even more used for the synthesis of complex
molecules.11−22 Less developed are C−H silylation and
hydroxymethylation, which in spite of their unquestionable
importance in organic synthesis,23−32 medicinal chemistry, and
pharmacy (Figure 1), their access remained governed by
transition-metal catalysis.
Because of the high nucleophilicity of silyl and hydroxyalkyl
radicals, they are good candidates to react with electron-
deficient heteroarenes rings. Unfortunately, the radical
silylation is generally low yielding and requires harsh reaction
conditions and stoichiometric amounts of oxidants. Addition-
ally, they suffer from substantial amounts of double silylated
products.33 Interestingly, some of these limitations have been
Received: August 26, 2020
Revised: October 28, 2020
https://dx.doi.org/10.1021/acscatal.0c03726
© XXXX American Chemical Society
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Figure 1. Representative biologically active silylated and hydroxymethylated compounds.
Scheme 1. Previous and Current Works for Silylation and Hydroxymethylation of Heteroarenes; (A) previous Investigations;
(B) this Work
C−H silylation and hydroxymethylation, respectively (Scheme
1).
carbamoyl radicals are predominantly formed and coupled with
1a to lead to the corresponding pyridines, which were detected
by NMR spectroscopy as major products. Next, the effect of
the base was evaluated, and only K2HPO4 gave good
conversion (entry 9, 63%), whereas very low or no reactions
were observed with both inorganic (entries 8, 10,11) and
organic bases (entry 12). Finally, the utility of the base,
photocatalyst, and light was ascertained as no reaction is
possible in their absence (entries 13−15).
As shown in Scheme 1b, the oxygen-centered radical, formed
upon single electron reduction of NPA by the excited state of
the photocatalyst, abstracts a hydrogen atom from silanes (Si−
H) or methanol (C−H) to generate the corresponding
nucleophilic silyl and hydroxymethyl radicals. These radicals
can then interact with NPAs to yield the corresponding
silylated and hydroxymethylated adducts after few subsequent
steps.
We next investigated the scope of the reaction (Figure 2). In
this context, we first examined the reactivity of N-
methoxypyridinium ions bearing para-substituted electron
donating groups. Interestingly, the reaction proceeds well,
and the silylated adducts were isolated in fair yields (3a−3c;
55−65%). Likewise, pyridines bearing electron-deficient
groups such as phenyl (3d, 75%), cyano (3e, 63%), and
carbonyl (3f, 67%) were obtained in good yields. However, the
protocol works less efficiently with the para-substituted
trifluoromethyl group as 3g was isolated in 38% yield. The
parent pyridine shows good reactivity (3h, 74%) and was
obtained as an equimolar mixture of the two regioisomers.
When 2-substituted pyridinium ions, bearing methoxy, cyano,
and chloro (1i−1k), were subjected to our optimized
conditions, the C2 and C4 regioisomers were obtained (ratio
≈ 1:1) in good combined yields (47−97%). Interestingly, each
of these isomers was isolated by column chromatography and
fully characterized (see Supporting Information). The
compatibility of our conditions with chloro-substituted
pyridine (3k) merits to be highlighted as it can lead to further
synthetic transformations. Given the synthetic relevance of 2-
aryl-silylated pyridines as precursors for the synthesis of
RESULTS AND DISCUSSION
■
With the working hypothesis outlined above (Scheme 1), we
studied the reaction of the pyridinium salt 1a with t-
butyldimethylsilane (tBuMe2SiH) 2a by investigating the effect
of the photocatalyst, the base, and the solvent. Interestingly,
and in contrast to previous studies, where excess of the silane is
required,27 our optimization studies showed that only one
equivalent of 2a with respect to two equivalents of 1a is
optimal for the feasibility of the reaction. Under these
conditions and by employing sodium bicarbonate as a base
in MeCN, the 3-phosphonated quinolinone (entry 3) and fac-
Ir(ppy)3 (entry 4) gave 62 and 75% conversion, respectively.
However, [Ru(bpy)3]2+or eosin Y were found to be ineffective
catalysts (Table 1, entries 1,2).
Keeping fac-Ir(ppy)3 as a photocatalyst and NaHCO3 as a
base, a solvent screening, including tetrahydrofuran (THF)
(entry 5, 8%), dimethylformamide (DMF) (entry 6, 3%) and
CH2Cl2 (entry 7, traces), was performed and showed
disappointing results. Indeed, due to the low bond dissociation
energy of C−H bonds of THF and DMF, the α-THF and
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a
Table 1. Optimization and Initial Studies of the Visible Light-Mediated Silylation
a
b
entry
photocatalyst (PC)
base
solvent
3a, yield [ %]
2+
1
2
3
4
5
6
7
8
Ru(bpy)3
Eosin Y
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
K2HPO4
K3PO4
MeCN
MeCN
MeCN
MeCN
THF
traces
0%
62
75
8
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
DMF
DCM
3
traces
23
63
24
6
0
0
9
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
15
Cs2CO3
Et3N
NaHCO3
fac-Ir(ppy)3
fac-Ir(ppy)3
c
NaHCO3
a
Reactions were performed by reacting N-methoxypyridinium 1a (0.22 mmol, 2 equiv) with t-butyldimethylsilane 2a (0.11 mmol, 1 equiv) in the
b
1
indicated solvent (4.4 mL) using blue LEDs (5 W) for 16 h. Yields were determined by H NMR spectroscopy of the crude mixture in the
presence of 1,1,2,2,-tetrachloroethane as the internal standard. Reaction carried out in the absence of light.
c
ligands, we subsequently applied our approach to 2-arylated N-
methoxypyridinium ions. Notably, the parent 2-phenyl (1m)
and para-methyl aryl pyridinium ions (1n) delivered both
silylated isomers in 79 and 80%, respectively, whereas the para-
methoxy and para-trifluoromethyl pyridinium ions (3o and
3p) gave both regioisomers along with the bis-silylated
adducts.
Quinolines were also compatible with our conditions, and 2-
and 4-silylated quinolines (3q−3s) were obtained in fair yields
(43−64%).
practically simple hydroxymethylation of a large variety of
quinolines and isoquinolines in the presence of substoichio-
metric amounts of Selectfluor.57 Unfortunately, pyridines were
found to be unreactive under their optimized conditions, thus
calling for an alternative approach which would be
complementary to Lei’s method. With this in mind, methanol
(4) was made to react with different N-methoxypyridinium
ions (1) under the optimized conditions described above
(Figure 2). Interestingly, the desired adducts were obtained in
good yields.
Importantly, this protocol was applied for the synthesis of
the biorelevant target 3t, which was obtained in comparable
overall yield to that obtained by Zhang et al.34 The chloro,
cyano, and ester functional groups remained intact, thus
allowing for further chemical transformations. Finally, the
reactions of other silanes with pyridinium ions 1 were also
tested and gave low to modest yields (3u−3x, 13−45%).
As outlined above, considering the omnipresence of the
methylol functional group in a large variety of biologically
active compounds and natural products, we examined our
photocatalytic approach combining N-methoxypyridinium ions
with methanol to synthesize hydroxymethylated pyridines
(Figure 3). It should be noted that Lei et al.57 reported a
As shown in Figure 3, 4-substituted pyridinium ions
delivered the alcohols (5a−5e) in 42−82% yields as single
isomers. Noteworthily mentioning, the (4-chloro-2-pyridinyl)-
methanol 5f, which is known as an inhibitor of gastric acid
secretion (Figure 1), was isolated in 66% yield.
As for the C−H silylation reaction, two regioisomers, in
almost 1:1 ratio, were obtained (5g−5l, 62−99% combined
yields) when the unsubstituted and 2-substituted pyridinium
salts were employed. A 41% yield has been obtained with the
3,5-dimethylpyridinium ion (5m), and the process works well
with quinolinium (5n, 5o).
Mechanistic Investigations. To gain more insights about
mechanisms of the two photocatalytic processes, a lumines-
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a
Figure 2. Scope of the photocatalytic silylation of heteroarenes. Standard conditions: N-alkoxypyridinium 1 (2 equiv) was combined with 2a (1
equiv) in the presence of fac-Ir(ppy)3 (2 mol %) and NaHCO3 (2 equiv) in CH3CN (0.05 M) using blue LEDs (5 W) for 16 h.
cence-quenching study was performed. The Stern−Volmer
fluorescence experiment showed that the excited state of fac-
Ir(ppy)3* is quenched by the pyridinium salt 1a, and a linear
relationship between the quenching efficiency and the
concentration of 1a was obtained (Figure S5, Supporting
Information). This indicates the ability of the photocatalyst in
its excited form [fac-Ir(ppy)3]* to activate the N−O bond of
1a.
We next characterized the key radical intermediates involved
in each photoreaction by spin-trapping electron paramagnetic
resonance spectroscopy. In this context, the combination of
fac-Ir(ppy)3 with 4-methyl N-methoxypyridinium ion in the
presence of N-tert-butyl-α-phenylnitrone (PBN) as a spin trap
and irradiated under blue light illumination (λmax = 420 nm)
showed a triplet of doublets (aN = 13.6 G; aH = 1.8 G), that is
characteristic of MeO−PBN adduct (Figure 4).58,59
formation of the silyl and hydroxymethyl radicals was
confirmed by electron paramagnetic resonance (EPR) spec-
troscopy. Indeed, the irradiation of a mixture of fac-Ir(ppy)3
and 4-methyl N-methoxypyridinium ion with methanol in the
presence of PBN gave rise to a signal that consists of a triplet of
doublets (aN = 13.9 G, aH = 2.1 G), which could be attributed
to the trapping of the hydroxymethyl-PBN radical (Figure 4),
in agreement with previous results reported by Durand.60
When the same EPR experiment was carried out with silane 2a
instead of methanol, the methoxyl-PBN radical was detected
along with a new radical species (aN = 15.0 G, aH = 4.3) that
could be assigned as the silyl-PBN radical (see Supporting
Information).61
The addition of the highly nucleophilic silyl radical (ω− =
0.75, for more details, see Supporting Information) at the C4
position of the pyridine ring proceeds with an activation energy
of 7.1 kcal/mol to give the radical species 6. Not surprisingly,
In accordance with our density-functional theory (DFT)
calculations (Figure 5) that revealed viable hydrogen atom
transfer reactions between (•OMe) and silane (2a; ΔG# = 12.1
kcal/mol) or methanol (4; ΔG# = 14.5 kcal/mol), the
the reaction of the less nucleophilic hydroxomethyl (ω−
=
0.66) radical at the C4 position is 2.2 kcal/mol slower than the
silyl addition. The weak difference in energy between the
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a
Figure 3. Scope of the photocatalytic hydroxymethylation of heteroarenes. Reaction conditions: N-alkoxypyridinium 1 (1 equiv) MeOH (5
equiv), fac-Ir(ppy)3 (2 mol %), and NaHCO3 (1 equiv) were reacted in CH3CN (0.05 M) under blue light irradiation (LEDs, 5 W) for 2 h.
Figure 4. EPR experiments for the trapping of the methoxyl and the hydroxymethyl radicals with PBN.
addition of radicals at the C2 and C4 positions (0.2−0.6 kcal/
mol) may account for the low experimental regioselectivity
(Figures 2 and 3). Both pathways, silylation and hydrox-
ymethylation, undergo a low barrier deprotonation to form the
radical species 7, which upon N−O bond homolysis yields the
desired product and generates a methoxy radical to persist a
new radical chain pathway. This hypothesis is supported by the
high reaction quantum yields of ϕ = 10 for silylation and ϕ =
21.2 for hydroxymethylation (for details, see Supporting
Information).
It should be pointed out at this stage that one important
factor for the feasibility of the Minisci reactions with NAPs is
the resistibility of the nucleophilic radical toward single-
electron oxidation. In fact, in a series of seminal contributions,
Farid and co-workers elucidated, through in-depth physical
organic investigations,62−64 the ability of NPAs to oxidize
alcohols into the corresponding carbonyl compounds under
photocatalytic conditions. It has been demonstrated that
energetic limitations of these chain propagations depend on
the reduction potential of the pyridinium salts and the
oxidation potential of the α-hydroxy radicals. It appears from
our studies on silylation and hydroxymethylation as well as
from previous work reported by the Hong group on alkylation,
acylation, and phosphorylation of heteroarenes55 that the
addition of the nucleophilic radicals into NPAs is irreversible
and faster than the oxidation of the radicals (X•) to form the
corresponding cations (X+) (Figure 4). Based on this
hypothesis, the low yields of the silylated pyridines 3u−3x
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Figure 5. Free energy profile for the photocatalytic silylation and hydroxymethylation, calculated at the SMD-(ACN)-M06-2X/def2-TZVP//
B3LYP/6-31+G(d) level of theory. Energies for the C2-regioisomer are given between brackets. For computational details, see Supporting
Information.
can be attributed to the oxidation of the silyl radicals. To
confirm this, we analyzed by NMR spectroscopy the silylation
of para-methyl NAP with triphenylsilane under the optimized
conditions and detected the formation of the methoxyltriphe-
nylsilane in good yield (see Supporting Information). This
adduct is formed upon addition of methanol, formed after
HAT of the methoxy radical with the triphenylsilyl cation
(Figure 5).
hydroxymethylation. Importantly, the scope of both reactions
is wide, tolerates many functionalities, and has further been
explored for the synthesis of biologically relevant products. A
combination of EPR spectroscopy and DFT allowed to
characterize silyl and hydroxymethyl radicals and even more
to understand factors controlling both photoreactions. These
practically simple and mild transformations are likely to be
useful for synthesizing privileged organic scaffolds.
CONCLUSIONS
■
The silylation and hydroxymethylation of heteroarenes are very
important reactions in various areas ranging from catalysis to
medicinal chemistry. While Minisci-type versions of those
reactions have been developed, they required the use of
external oxidants and Bronsted acids to activate the
heteroarenes. Taking advantage of the dual reactivity of
NPAs as hydrogen atom abstractors under photoredox
conditions and as electrophiles, we demonstrate herein the
ability of those salts to promote C−H silylation and
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c03726.
General experimental procedures and analytic data of
new compounds (1H, 13C, and 19F NMR spectra), EPR
experiments, and DFT calculations (PDF)
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AUTHOR INFORMATION
Corresponding Author
Sami Lakhdar − Université Paul Sabatier, Laboratoire
Hétérochimie Fondamentale et Appliquée (LHFA, UMR
5069), 31062 Toulouse Cedex 09, France; orcid.org/
0000-0002-1168-7472; Email: lakhdar@chimie.ups-tlse.fr
■
̈
(7) Marzo, L.; Pagire, S. K.; Reiser, O.; Konig, B. Visible-Light
Photocatalysis: Does It Make a Difference in Organic Synthesis?
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Chem., Int. Ed. 2012, 51, 6828−6838.
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527−532.
Fatima Rammal − Normandie Université, LCMT,
ENSICAEN, UNICAEN, CNRS, 14000 Caen, France
Di Gao − Normandie Université, LCMT, ENSICAEN,
UNICAEN, CNRS, 14000 Caen, France
Sondes Boujnah − Normandie Université, LCMT,
ENSICAEN, UNICAEN, CNRS, 14000 Caen, France
Aqeel A. Hussein − College of Dentistry, University of Al-
Ameed, Karbala, Iraq
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Commun. 2019, 55, 466−469.
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V.; Tudge, M. Late-Stage Functionalization of Biologically Active
Heterocycles through Photoredox Catalysis. Angew. Chem., Int. Ed.
2014, 53, 4802−4806.
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Jacques Lalevee − Université de Haute-Alsace, CNRS, IS2M
UMR 7361, F-68100 Mulhouse, France; orcid.org/0000-
0001-9297-0335
(13) Wang, Z.; Ji, X.; Han, T.; Deng, G.-J.; Huang, H. LiBr-
Promoted Photoredox Minisci-Type Alkylations of Quinolines with
Ethers. Adv. Synth. Catal. 2019, 361, 5643−5647.
Annie-Claude Gaumont − Normandie Université, LCMT,
ENSICAEN, UNICAEN, CNRS, 14000 Caen, France
Fabrice Morlet-Savary − Université de Haute-Alsace, CNRS,
IS2M UMR 7361, F-68100 Mulhouse, France
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Complete contact information is available at:
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(15) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy
for the Visible-Light-Mediated Generation of Alkyl Radicals. Angew.
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Minisci-Type Alkylation of N-Heteroarenes with Alkanes with High
Methylene Selectivity. ACS Catal. 2018, 8, 11847−11853.
F.R., D.G., and S.B. performed the photocatalytic reactions,
characterized the final products, and measured quantum yields.
A.A.H. carried out the DFT calculations and F.M.-S.
conducted EPR experiments. S.L. designed the project and
wrote the manuscript.
́
́
(17) Gutierrez-Bonet, A.; Remeur, C.; Matsui, J. K.; Molander, G. A.
Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via
Oxidative Homolysis of 1,4-Dihydropyridines. J. Am. Chem. Soc. 2017,
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Notes
The authors declare no competing financial interest.
(18) Matsui, J. K.; Primer, D. N.; Molander, G. A. Metal-Free C-H
Alkylation of Heteroarenes with Alkyltrifluoroborates: A General
Protocol for 1°, 2° and 3° Alkylation. Chem. Sci. 2017, 8, 3512−3522.
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ACKNOWLEDGMENTS
The authors thank the Centre National de la Recherche
Scientifique, Labex Synorg (ANR-11-LABX-0029), and
■
́
Normandie Universite for financial support. F.R. is grateful
to the French Ministry of Research for a doctoral scholarship.
The authors acknowledge the University of Southampton for
the computational resources (iridis4 supercomputers).
DEDICATION
■
This paper is dedicated in memory of our friend and colleague
Franco
̧
is Couty (Institut Lavoisier Versailles).
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