Site-selective c-h acylation of pyridinium derivatives by photoredox catalysis

Article abstract of DOI:10.1021/acscatal.9b03367

A strategy for visible-light-induced site-selective C-H acylation of pyridinium salts was developed by employing N-methoxy-or N-aminopyridinium salts, offering a powerful synthetic tool for accessing highly valuable C2- A nd C4-acylated pyridines. The met

Full text of DOI:10.1021/acscatal.9b03367

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Article
Site-Selective C–H Acylation of Pyridinium
Derivatives by Photoredox Catalysis
Sungwoo Jung, Hyeonyeong LEE, Yonghoon Moon, Hoi-Yun Jung, and Sungwoo Hong
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03367 • Publication Date (Web): 20 Sep 2019
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Site-Selective C–H Acylation of Pyridinium Derivatives by
Photoredox Catalysis
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Sungwoo Jung,a,b Hyeonyeong Lee,a,b Yonghoon Moon, a,b Hoi-Yun Jung,a,b Sungwoo Hong,b,a,*
aDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
bCenter for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
ABSTRACT: A strategy for visible-light-induced site-selective C–H acylation of pyridinium salts was developed by employing N-
methoxy- or N-aminopyridinium salts, offering a powerful synthetic tool for accessing highly valuable C2- and C4-acylated
pyridines. The methoxy or amidyl radicals photocatalytically generated from the pyridinium salts can undergo hydrogen atom
abstraction from readily available aldehydes to form acyl radicals, which can engage in addition to pyridinium substrates.
Remarkably, the use of N-methoxypyridinium salts preferentially gives the C2-acylated pyridines, and the site selectivity can be
switched from C2 to C4 by using N-aminopyridinium salts. The utility of this transformation was further demonstrated by the late-
stage functionalization of complex biorelevant molecules and by application of acyl radicals to photocatalytic radical cascades.
KEYWORDS: photochemistry, acyl radical, acylated pyridine, site-selectivity, pyridinium salt.
Acyl pyridines are frequently used as privileged cores in the
pharmaceutical and fine chemical research fields.1 Unlike
electron-rich (hetero)arenes, acylation of the pyridine core via
the conventional Friedel–Crafts reaction is fundamentally
problematic due to the decreased electron density in the
aromatic system and the addition of an acylating agent to the
nitrogen atom,2 which requires a nonclassical strategy. The
pyridine scaffold contains multiple reactive sites, and selective
functionalization of pyridines can afford a powerful synthetic
method for access to chemical modification of the pyridine-
containing biorelevant compounds.3,4 As a result, there is a
growing demand for synthetic methods that can site-
selectively functionalize pyridine derivatives in a predictable
and controllable manner under mild conditions. Importantly,
several approaches have achieved functionalization of the C2
position of the pyridine core using pyridine N-oxides.5 For
example, the Murakami group demonstrated the
photocatalyzed C2-alkylation of pyridine N-oxides through the
cleavage of cyclized radical cation intermediates (Scheme
1a).5a Using alkynes as acyl group precursors, Singh et al.
reported the Ag-catalyzed oxidative acylation of pyridine N-
oxides.5b Furthermore, the photoinduced divergent C2-
alkylation and acylation of pyridine N-oxides with alkynes
were achieved by the Wu group.5c
Despite these advances, these reactions remain limited
mainly to the introduction of the acyl group to the C2-position
of the pyridine moiety, and the introduction of a carbonyl
group at the C4-position of pyridines remains a challenge and
has yet to be realized with meaningful selectivity.6 In this
context, the development of a mild method that enables the
controlled acylation of the specific C–H bonds in pyridine
scaffolds (C2 vs. C4) is highly desirable. Acyl radicals are
versatile and useful intermediates for a broad range of
chemical reactions.7 For the direct generation of acyl radicals
from readily available aldehydes, the photochemical approach
has been proposed as a green route, which could be employed
to drive Giese-type addition to activated alkenes and Minisci-
type acylation of heteroarenes (e.g., isoquinoline).8 To convert
aldehydes into acyl radicals, radical species generated from
Scheme 1. Design Plan for the Site-Selective Acylation of
Pyridine Scaffolds
a) C2 selective alkylation/acylation of pyridine N-oxides (ref 5a,b,c)
Murakami, 2018
Singh, 2018
R2
R1
R1
R
R
R
R1
R1
+
or
N
O
N
O
N
R2
Wu, 2019
via
O
O
N
R
N
R2
R
R1
or
R2
N
R1
H
R1
O
b) This work: N-Substituent-controlled site-selective acylation
O
PC
O
PC
X = OMe
N
H
X = NMeTs
N
O
X
N
C2 selective
C4 selective
site-selectivity control
acyl radical generation
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hydrogen atom transfer (HAT) reagents such as persulfates
aminopyridinium salt 1a and p-anisaldehyde 2a as model
substrates under blue LED irradiation (Table 1). After
evaluating some potential catalytic systems, we found that
irradiation of the reaction mixture enabled the direct C4-
acylation to afford the corresponding product 3a (entry 1). The
choice of base was critical for the reaction efficiency, and the
use of NaOAc dramatically promoted the formation of 3a
(entries 1-3). Of the various photocatalysts tested,
[Ir(dF(CF3)ppy)2bpy]PF6 was most effective in terms of
overall conversion and site selectivity (entries 3-6). Among
the solvents screened, 1,2-DCE was most effective for this
coupling reaction (entries 3, 7 and 8). We examined the
influence of the light source, and blue LEDs gave the highest
yield (see the Scheme S2 for details). After a systematic
screening, the desired product 3a was formed in 84% yield
with the optimal conditions (entry 3). Mild room temperature
conditions were sufficient for the construction of the scaffolds
in the overall reaction process. Control experiments
demonstrated that the photocatalyst and visible light were
required for the successful reaction (entries 9 and 10). In the
presence of TEMPO under optimal conditions, the desired
product was not obtained, indicating that the possible
involvement of radical intermediate in the reaction (entry 11).
Stern–Volmer quenching experiments were performed with
pyridinium salt 1a, revealing that the quenching rate was
directly proportional to the concentration of 1a and the
oxidative quenching cycle is presumably favored (see the
Figure S1 and S2 for details).
and peroxides are generally required to abstract the hydrogen
atom from the aldehyde.9 Recently, quinuclidine has emerged
as a HAT organocatalyst that efficiently abstracts the
aldehydic hydrogen atom to form the acyl radical.10
Furthermore, Wu and coworkers demonstrated that excited
Eosin Y directly abstracts the hydrogen atom from aldehydes
to form acyl radicals.11
Drawing inspiration from photocatalyzed radical reactions,
we imagined the possibility of controlling the reaction sites by
tuning the steric and electronic differences of the pyridinium
salts, which can differentiate and amplify the site-
discriminating interactions with acyl radicals. We speculated
that the oxo functionality of the acyl radical could engage in
the electrostatic attraction with the nitrogen of N-methoxy
pyridinium salt12,13 to afford C2-acylated pyridines, and this
intrinsic preference could be overcome by the use of N-
aminopyridinium salt to avoid an unfavorable clash at the C2
position between the N-methyl tosyl group and the
approaching acyl radical. In addition, we questioned whether
the methoxy or amidyl radicals14 generated from the
fragmentation of the pyridinium salts could function as
efficient HAT reagents by abstracting a hydrogen atom from
an aldehyde. Considering that the bond dissociation energy
(BDE) of the C–H of aldehydes is approximately 88 kcal/mol,
the BDEs of the O–H bond in MeOH (~104 kcal/mol) and the
N–H bond in TsNHMe (~101 kcal/mol) are large enough to
engage in a HAT event with an aldehyde.15 As outlined in
Scheme 1b, we discovered that the N-substituent of
pyridinium salts is capable of determining the reaction site in
the acylation reactions: N-aminopyridinium salts display a
strong preference for the C4-position, whereas N-
methoxypyridinium salts favor the addition of acyl radicals to
the C2-position.
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Scheme
2.
C4-Selective
Acylation
Using
N-
Aminopyridinium Salts a
Table 1. Optimization for Reaction Conditionsa
O
O
PC (1.0 mol%)
Ph
base (1.2 equiv)
H
Ph
N
N
+
-BF4
Me
solvent, rt, N2
blue LED, 24 h
N
OMe
MeO
Ts
2a
3a
1a
entry
photocatalyst
base
solvent
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
MeCN
yield(%)b
1
2
3
4
5
6
7
8
[Ir(dF(CF3)ppy)2bpy]PF6
[Ir(dF(CF3)ppy)2bpy]PF6
[Ir(dF(CF3)ppy)2bpy]PF6
Ir(ppy)3
-
30
59
84
24
23
68
79
33
NaHCO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Ru(bpy)3Cl2∙6H2O
EosinY
[Ir(dF(CF3)ppy)2bpy]PF6
[Ir(dF(CF3)ppy)2bpy]PF6
1,4-
dioxane
9
-
NaOAc
NaOAc
NaOAc
1,2-DCE
1,2-DCE
1,2-DCE
NR
NR
NR
10c
11d
[Ir(dF(CF3)ppy)2bpy]PF6
[Ir(dF(CF3)ppy)2bpy]PF6
aReaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), photocatalyst (1.0
mol%), base (0.12 mmol), and solvent (1.0 mL) with blue LED irradiation
under N2 atmosphere at rt for 24 h. bThe yields were determined by 1H
NMR with an internal standard. cReaction was performed in the dark.
dTEMPO (3.0 equiv) was added.
To test the feasibility of our proposed approach, we initially
investigated the photocatalytic reaction using N-
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O
[Ir(dF(CF3)ppy)2bpy]PF6 (1.0 mol%)
NaOAc (1.2 equiv)
Scheme
3.
C2-Selective
Acylation
Using
N-
R
O
2
R
Methoxypyridinium Saltsa
+
-BF4
N
N
1
H
N
1,2-DCE (0.1 M), rt, N2
blue LED, 24 h
O
Me
Ts
[Ir(dF(CF3)ppy)2bpy]PF6 (1.0 mol%)
NaOAc (1.2 equiv)
3
O
R
N
-BF4
N
+
O
O
O
H
R
1,2-DCE (0.1 M), rt, N2
blue LED, 24 h
OMe
Ph
Ph
Ph
5
2
4
N
N
N
O
O
O
MeO
Me
tBu
N
Ph
N
Ph
N
Ph
Ph
3a
3b
3c
3f
, 82% (single)
75%b
O
, 70% (single)
O
, 72% (36:1)
O
MeO
Me
tBu
10
11
12
13
14
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5c
, 81% (8.0:1)
5b
, 81% (8.0:1)
5a
, 83% (9.4:1)
Ph
Ph
Ph
O
O
O
N
O
N
N
N
N
Me
O
N
Ph
Ph
F
3d
, 57% (single)
O
3e
, 65% (single)
, 58% (18:1)
O
F
Cl
O
O
5d
5e
, 71% (7.9:1)
O
, 67% (7.0:1)
5f
, 66% (8.0:1)
Ph
Me
Ph
Me
tBu
Ph
Ph
Ph
O
N
N
N
N
N
N
N
Cl
MeO
, 72%c (single)
3g
3i
, 58% (12:1)
, 65% (15:1)
3h
O
O
, 80%b,c (single) CN
5h
, 62%b (single)
Me
O
CN
5g
Me
Ph
Ph
O
O
O
Ph
6
Me
N
Ph
Me
N
Ph
Ph
N
Ph
N
N
, 77%c (single)
O
3k
3l
, 72% (11:1)
, 78% (18.5:1)
O
3j
5i
, 86% (2.5:1)
Me
5j
, 70% (4.4:1)
5k
, 86% (4.4:1)
O
OH
Me
O
O
N
Me
Ph
Ph
O
Me
Me
S
Ph
N
tBu
N
Ph
N
N
, 81%c (single)
3m
, 50% (single)
O
3n
, 70% (single)
3o
5l
, 76% (5.9:1)
O
5m
5n
, 67% (3.6:1)
, 90% (3.6:1)
R
O
O
O
N
O
N
OMe
N
Me
MeO
OMe
N
N
3p,
3q
R = OMe, 63% (19:1)
MeO
MeO
, 98%c (single)
3r
, R = CF3, 72% (23:1)
MeO
MeO
MeO
5p
, 80% (7.0:1)
5o
, 70% (5.7:1)
O
5q
, 63% (single)
O
O
Ph
O
O
N
O
N
Ph
N
N
N
N
MeO
MeO
3s
3u
, 70% (2.8:1)
, 57% (7.1:1)
3t
, 79% (4.6:1)
MeO
MeO
5t
aReaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), PC (1.0 mol%), base
(0.12 mmol), and solvent (1.0 mL) with blue LED irradiation under N2 at
rt for 24 h. Yields of isolated products. Isomeric ratios were determined by
Me
, 72% (single)
O
Ph
O
OMe
, 74%b (single)
, 89%b (single)
5r
5s
O
O
1H NMR analysis. b1.0 mmol scale. 2 was used as the limiting reagent
c
O
N
N
with 1 (2.0 equiv) in MeCN (0.1 M).
MeO
5v
MeO
N
MeO
CF3
CN
, 81%b (single)
, 97%b (single)
5w
, 61% (single)
5u
The simple optimized reaction conditions were then applied
to a variety of aldehydes to establish the scope and generality
of this method. As summarized in Scheme 2, a range of
benzaldehydes bearing methoxy, methyl, butyl, ester, fluoro,
and chloro groups were successfully engaged to afford the
desired products with excellent C4-regiocontrol (3a-3g). We
subsequently assessed the applicability of the current method
with respect to various aliphatic aldehydes, and the utility of
the present method was demonstrated by providing convenient
access to prominent structural motifs featuring acyl pyridine
units containing either linear or branched alkyl chains (3h-3l).
Notably, alkyl aldehydes bearing alcohol, thioether,
cyclopropyl groups were well tolerated in the present cross-
coupling reactions and provided the desired ketones 3m, 3n,
and 3o, thereby significantly expanding the scope and
synthetic utility of this reaction. In addition, we were pleased
to observe that pyridyl groups possessing methoxy- or
trifluoromethyl-substituted aryl (3p, 3q) and ester (3r) groups
reacted well to afford the desired C4-acylated pyridines under
the optimized reaction conditions. The reaction with a
substrate bearing C3-phenyl group provided a modest
preference for the C4-acylated product (3u, 2.8:1 selectivity).
aReaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), PC (1.0 mol%), base
(0.12 mmol), and solvent (1.0 mL) with blue LED irradiation under N2 at
rt for 24 h. Yields of isolated products. Isomeric ratios were determined by
1H NMR analysis. 2 was used as the limiting reagent with 1’ (2.0 equiv)
b
in MeCN (0.1 M). c(NH4)HCO3 was used instead of NaOAc.
Encouraged by the exciting results from C4-selective
acylation, we next directed our attention to C2-selective
acylation by investigating other N-substituents of pyridinium
salts as summarized in Scheme 3. Remarkably, by switching
the N-substituent to a methoxy group, the site selectivity
changed from the C4-position to C2-position of the pyridine
scaffold. Subsequently, the scope of this method was studied
with respect to various benzaldehydes bearing either electron-
rich or electron-deficient substituents, which successfully
reacted with the pyridinium salts to afford the desired C2-
acylated products (5a-5h). In a similar fashion, the current
protocol can be extended to aliphatic aldehydes, affording the
C2-acylated pyridine derivatives (5i-5n). In addition, pyridyl
groups possessing methyl, methoxy, ketone, ester, cyano, and
trifluoromethyl substituents reacted well to afford the desired
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acylated pyridines with excellent C2-regiocontrol under the
optimized reaction conditions (5o-5v).
Scheme 5. Photocatalytic Cascade Construction of
Functionalized Oxindole
To further highlight the broad applicability of this site-
selective synthetic method, we carried out the late-stage
modifications of pharmaceutically relevant molecules. As
illustrated in Scheme 4, when the aldehyde 6 derived from
adapalene was subjected to the standard reaction conditions,
site-selective acylation of the pyridinium scaffolds occurred
under the present catalytic systems to yield the corresponding
C4- and C2-products 7 and 8, respectively with good
functional group tolerance. In a similar manner, the site-
selective acylation proceeded well when we applied the
standard conditions to pyridinium compounds 9 derived from
vismodegib.
4
5
6
7
8
9
OMe
O
Me
H
O
Me
N
O
MeO
Me
+
conditions
2a
O
N
BF4
Me
N
X
10
11
12
13
14
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12
, X = OMe, 58%
= NTs(Me), 40%
Having demonstrated the ability of the current photocatalytic
system to generate acyl radicals, we next ventured to explore
more challenging radical cascades to construct structurally
complex pyridine-tethered chromanones. To this end, we
prepared aldehyde substrates 13 linked to olefin chains, as
illustrated in Scheme 6, which were subjected to the optimized
conditions in the presence of pyridinium salt 4. To our delight,
the proposed cascade reactions comprising acyl radical
formation, intramolecular radical cyclization, and interception
by a pyridinium salt enable the rapid generation of valuable
pyridine-tethered chroman-4-ones (14a-14c) and related
derivatives (14d-14f).
Scheme 4. Late-Stage Site-Selective C-H Acylation of
Complex Molecules
from adapalene
MeO
O
H
conditions
O
MeO
-BF4
+
N
Ph
X = NTs(Me)
X
7
, 50% (single)
6
N
Ph
MeO
Scheme 6. Application to Radical Cascades
conditions
X = OMe
R
O
O
X
N
Ph
N
R
conditionsa
H
+
R
8
, 43% (7.2:1)
O
R
BF4
N
n
n
X
OMe
4
O
from vismodegib
Cl
13
14
O
Cl
X = O, C, N
n = 0,1
O
R
N
N
n
X
N
H
N
conditions
Me
H
S
O
Cl
O
O
Me
N
-BF4
X = NTs(Me)
O
O
X
S
Cl
O
N
O
9
N
O
O
+
10
, 71% (single)
O
MeO
O
O
O
H
CN
COOMe
N
14b
, 52%
14a
, 56%
O
Ph
14c
, 48%
O
Cl
N
O
O
MeO
O
conditions
2a
N
N
Me
N
H
X = OMe
Me
S
Cl
OMe
O
N
O
O
11, 54% (2.4:1)
CN
CN
Boc
CN
14d
, 55%
14e
, 57%
14f
, 56%
aReaction
conditions:
13
(0.1
mmol),
4
(0.2
mmol),
To clarify the reaction mechanism, several control
experiments were performed. To determine whether the
pyridine generated in situ by single electron transfer (SET)
during the reaction could act as a substrate, we subjected
mixtures of pyridinium salt 1a and methyl nicotinate to the
standard reaction conditions (see the Scheme S4 for the
details). As anticipated, it was observed that only pyridinium
salt 1a was converted into the corresponding product 3a. Next,
the crucial step of the proposed mechanism is the
photogeneration of acyl radicals by the HAT process from
aldehydes to methoxy or amidyl radicals. In the presence of
2,4,6-trimethyl substituted pyridinium salt, the intermolecular
acylation of an olefin and an intramolecular radical cyclization
readily proceeded16, leading to the formation of oxindole 12
(Scheme 5). These results validate that acyl radicals can be
efficiently generated from aldehydes under the current
catalytic system where both N-methoxy- and N-
aminopyridinium salts serve as efficient HAT reagents.
[Ir(dF(CF3)ppy)2bpy]PF6 (2.5 mol%), NaHCO3 (0.12 mmol), and MeCN
(1.0 mL) at rt under N2 for 16 h with blue LED irradiation. Yields of
isolated products.
To gain more insight into the observed selectivity, density
functional theory (DFT) calculations were carried out (see the
SI for computational details). The site-selectivity is
determined in the acyl radical addition step. In the case of the
N-methoxypyridinium salts, our calculations indicate that the
transition state leading to the C2-product is 1.4 kcal/mol lower
in energy than the TS for the C4-product (Figure S8) because
of attractive electrostatic interactions between the positively
charged nitrogen atom of the N-methoxypyridinium substrate
and oxo functionality of the acyl radical.13 On the other hand,
the N-methyl tosyl substituents on the N-amidopyridinium salt
is sterically too bulky to allow the acyl radical to engage in
favorable electrostatic attractions. As shown in Figure S9, the
TS for the C4-product is found to be 2.4 kcal/mol lower in
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energy than the TS affording the C2-product, which can be
radicals that can be applied to other photocatalytic radical
cascades.
attributed to the greater steric demand of N-methyl tosyl group.
In addition, when we conducted control experiments by
subjecting substrates bearing a sterically smaller mesyl group,
the site-selectivity was dramatically reduced (C4/C2 = 3.5:1),
indicating the influence of substituents on site-selectivity (see
the Scheme S7 for details).
AUTHOR INFORMATION
Corresponding Author
*E-mail: hongorg@kaist.ac.kr
A plausible mechanism for the current methods is proposed
in Figure 1. The photoexcited Ir(III)-photocatalyst under blue
LED irradiation undergoes the SET reduction of the N-alkoxy-
or N-amino-pyridinium salt to generate the alkoxy or amidyl
radicals. These radicals subsequently abstract the hydrogen
atom from the aldehyde substrate to generate the acyl radical
species B. Afterward, the acyl radical engages in cross-
coupling with another pyridinium substrate to form radical
intermediate C, which undergoes deprotonation and N-
heteroatom bond cleavage to form the final product and
release another alkoxy or amidyl radicals. The resultant radical
initiates the radical chain pathway by generating the acyl
radical. The quantum yield was determined to be relatively
high at Φ = 18.7 (see the SI for the details), which indicates
that the radical chain pathway is quite productive. In the
process, an alternate reaction pathway involving
rearomatization and reduction by SET events in the
photoredox catalytic cycle can be envisioned to maintain the
catalytic cycle. In both pathways, the base is required to
deprotonate intermediates C, leading to the final products.
ORCID
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Sungwoo Hong: 0000-0001-9371-1730
ASSOCIATED CONTENT
Supporting Information
Experimental procedure and characterization of new compounds
(1H and 13C NMR spectra). This material is available free of
charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
This research was supported financially by Institute for Basic
Science (IBS-R010-A2).
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O
R
N
N
or
N
[PC]*
PC
Me
Ts
OMe
R
A
or
N
O
OMe
N
N
SET
O
SET
Me
Ts
OMe
•
•+
OMe
•
PC
R
H
or
•
or
•
N
Me
- H+
N
A
Ts
PC*
Me
Ts
MeOH
or
+
•+
PC
H
N
O
R
O
Me
Ts
product
H
H
•
R
R
or
chain
pathway
N
B
N
N
O
OMe
C
Me
Ts
•
O
- H+
N
Me
Ts
or
OMe
product
R
H
•
Figure 1. Plausible reaction mechanism
In summary, the use of pyridinium salts as both efficient
HAT reagents and pyridine surrogates leads to photocatalytic
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selectivity can be switched from C2 to C4 by using N-
aminopyridinium salts. This convenient and versatile method
does not require an oxidant, and the utility of this
transformation was further demonstrated by the late-stage
functionalization of complex biorelevant molecules.
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the current photocatalytic system provides access to acyl
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Perfluoroarylation
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X = OMe
N
H
X = NMeTs
N
O
HAT
X
N
C2 selective
C4 selective
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