ortho-Alkylation of Pyridine N-Oxides with Alkynes by Photocatalysis: Pyridine N-Oxide as a Redox Auxiliary

Article abstract of DOI:10.1002/chem.201901065

A photocatalyzed ortho-alkylation of pyridine N-oxide with ynamides and arylacetylenes has been developed, which yields a series of α-(2-pyridinyl) benzyl amides/ketones. Mechanistic studies, including electrochemical studies, radical-trapping experiments, and Stern–Volmer fluorescence quenching studies demonstrate that pyridine N-oxide serves as both a redox auxiliary and radical acceptor to achieve the mild photocatalytic single-electron oxidation of carbon–carbon triple bonds with the generation of a cationic vinyl radical intermediate.

Full text of DOI:10.1002/chem.201901065

A Journal of
Accepted Article
Title: ortho-Alkylation of Pyridine N-oxides with Alkynes by
Photocatalysis: Pyridine N-oxide as Redox Auxiliary
Authors: Jonathan P Markham, Ban Wang, Edwin D Stevens, Stuart C
Burris, and Yongming Deng
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201901065
Link to VoR: http://dx.doi.org/10.1002/chem.201901065
Supported by

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
ortho-Alkylation of Pyridine N-oxides with Alkynes by
Photocatalysis: Pyridine N-oxide as Redox Auxiliary
Jonathan P. Markham, Ban Wang, Edwin D. Stevens, Stuart C. Burris and Yongming Deng*
Dedicated to Professor Hong Wang on the occasion of her 50th birthday
Abstract: A photocatalyzed ortho-alkylation of pyridine N-oxide with
ynamides and arylacetylenes has been developed, yielding a series
a)
b)
Underdeveloped catalytic generation of alkyne cation radicals
- e-
of α-(2-pyridinyl) benzyl amides/ketones. Mechanistic studies,
including electrochemical studies, radical-trapping experiments, and
Stern–Volmer fluorescence quenching studies demonstrate pyridine
N-oxide serves as both a redox auxiliary and radical acceptor to
achieve the mild photocatalytic single-electron oxidation of carbon-
carbon triple bonds with the generation of cationic vinyl radical
intermediate.
R1
R2
R1
R2
catalyst
This research
R1
pyridine N-oxide
as redox auxiliary and reactant
R2
R1
R2
photocatalyst (PC), hv
N
O
N
O
Introduction
R1
R2
R1
R2
PC, hv
N
O
Over the past decade, the development of photocatalysis in
organic synthesis has enabled the invention of new activation
modes for organic substrates and delivered a wide variety of
N
O
N
O
R1
R2
oxidizable adduct
nontraditional
bond-forming
protocols
and
synthetic
methodologies.[1] The Nicewicz group and others demonstrate a
series of photocatalyzed anti-Markovnikov hydrofunctionalization
reactions through alkene cation radicals, which are generated
from alkene via photocatalyzed single-electron oxidation.[2] Most
recently the study of photocatalyzed single-electron oxidation of
aromatic substrates to arene cation radicals delivers arene C-H
functionalization and substitution reactions.[3]
Alternatively, alkyne cation radicals, which can be directly
generated from carbon-carbon triple bond by single-electron
oxidation, presents an appealing intermediate for the construction
of carbon−carbon and carbon−heteroatom bonds (Scheme 1a).[4]
However, the achievement of alkyne single-electron oxidation and
its application in synthetically meaningful organic transformations
has yet to be accomplished in a catalytic manner.[5] This dearth of
methods is a result of the high oxidation potential of
carbon−carbon triple bonds, that requires a potent oxidant to
generate alkyne cation radicals.[6] In addition, the exceptionally
high reactivity of alkyne cation radicals makes them challenging
intermediates for the development of selective and meaningful
organic synthesis.[5,6] Reported approaches for the direct single-
electron oxidation of alkynes is limited to γ-irradiation[7] or the use
of strongly oxidizing conditions.[8] These conditions often result in
u n s e l e c t i v e , l o w y i e l d i n g s i d e r e a c t i o n s
Scheme 1. Underdeveloped catalytic single-electron oxidation of alkyne (a),
and this research: photocatalyzed ortho-alkylation of pyridine N-oxide with
alkynes (b). (PC = photocatalyst)
and dimerizations.[7a,b,8] The development of requisite
methodologies to achieve catalytic single-electron oxidation of
alkynes and the correlated organic transformations under mild
conditions is of great interest and in demand, yet challenging.
Herein, we present a strategy to address this long-standing
challenge by using pyridine N-oxide as a redox auxiliary to allow
the mild photocatalytic single-electron oxidation of carbon-carbon
triple bonds (Scheme 1b). Based on this strategy, we have
developed a visible-light photocatalyzed ortho-alkylation of
pyridine N-oxide with alkynes, in which the pyridine N-oxide also
serves as an oxygen transfer agent and radical acceptor. The
reaction proceeds on a range of ynamides, aryl alkynes and
substituted pyridine N-oxides that yields a series of α-(2-pyridinyl)
benzyl amides/ketones which are important skeletons in many
biologically active natural products and pharmaceuticals.[9]
The use of a redox trigger to alter the requisite
electrochemical potential of trifluoroacetic anhydride (TFAA) for
the development of a photocatalyzed trifluoromethylation reaction
was recently reported by Stephenson (Scheme 2a).[10] In this
study, a reducible adduct formed through an acylation between
TFAA and the redox trigger, pyridine N-oxide, enable the access
to CF3 radical by photocatalysis. We wondered whether it would
be possible to append a redox auxiliary in concert with alkynes to
assemble an oxidizable alkyne adduct. This could allow the
single-electron oxidation at a less-forcing potential that falls into
the redox potential window of readily accessible photocatalysts
(Scheme 2b). As part of the implementation of this research,
[a]
J. P. Markham, B. Wang, Dr. E. D. Stevens, Dr. S. C. Burris and Dr.
Y. Deng
Chemistry Department, Western Kentucky University
1906 College Heights Boulevard, Bowling Green, Kentucky 42101
E-mail: yongming.deng@wku.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.2018xxxxx.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
a)
Photochemical trifluoromethylation with pyridine N-oxide as redox trigger
ynamide and pyridine N-oxide. However, no visible color change
was observed, and no charge-transfer band was detected by UV-
vis absorption analysis of the ynamide and pyridine N-oxide
system. This result implies a weak non-chromogenic interaction
between 1a and pyridine N-oxide. An 1H NMR study of the
combination also indicated a possible association (Figure S2), but
their precise interaction remains unknown. The π-π interaction
between the phenyl group/triple bond of ynamide 1a and pyridine
N-oxide is also possible.[18]
O
O
CF3
Ar
F
3C
O
+
CF3
Ar
O
PC
CF3
N
O
CF3
pyridine
N
reducible TFAA adduct
O
b)
Proposed redox auxiliary promoted single-electron oxidation of alkynes
R1 R2
PC
R1
R2
R1
R2
_
_
+
e
Y
X
Y
X
Y
X
oxidizable
redox auxiliary
alkyne adduct
O
O
R1
R2
Ph
N
oxidation onset = 1.32 V
Y
X
N
O
Scheme 2. a) Stephenson’s photocatalyzed trifluoromethylation. b) Proposed
single-electron oxidation of carbon-carbon triple bond with redox auxiliary.
we took into account aspects of the non-covalent electrostatic
interactions between a polarized alkyne and a polarized or
charged substance, which has been long recognized.[11] Such
electrostatic interaction initializes the halogen addition step in the
alkynyl halo-Prins reaction[12] and stimulates the step-wise
cycloadditions of triple bonds and dipoles.[13] We postulated that
the non-covalent interactions may drive the reversible assembly
of a polarized alkyne and a polarized or charged redox auxiliary
to the oxidizable adduct. In this regard, ynamide, possessing
strongly polarized triple bond with amide substituent,[14] was
identified as the model substrate. Additionally, we proposed that
the use of an auxiliary bearing electron rich substructure could
serve as an electron donor to enhance the electrostatic
interactions with the electron poor triple bond of ynamide.
Furthermore, it would reduce the oxidation potential of the overall
adduct. Noteworthy, the exceedingly high oxidation potentials of
heteroaromatic N-oxides (pyridine N-oxide, Eox = 4.37 vs Li/Li+)
help to suppress the direct oxidation of themselves.[15] Herein,
pyridine N-oxide bearing a formally negatively charged oxygen,[16]
emerged to be the potential redox auxiliary for this investigation.
Figure 1. Voltammetry measurements of ynamide 1a/pyridine N-oxide system.
Cyclic voltammetry measurements of ynamide 1a (0.01 M in MeCN) and the
mixed solution of ynamide 1a (0.01 M in MeCN)/pyridine N-oxide 2a (0.01 M in
MeCN) were performed with a PARSTAT 2263 Advanced Electrochemical
System. Measurements were performed with a glassy carbon working electrode,
Pt auxiliary electrode, Ag/AgCl reference electrode, Bu4NPF6 electrolyte (0.1 M
in MeCN), and analytes (ynamide 1a, 0.01 M or 1a: 2a = 1:1, 0.01M for each)
with a sweep rate of 10 mV s-1. (MeCN = acetonitrile)
The mild oxidation potential of the ynamide/pyridine N-oxide
system (oxidation onset at 1.37 V vs SCE) suggests the
accessibility for the single-electron oxidation process by utilizing
red
photocatalysts, such as methylene blue (E*1/2
= 1.56 vs
SCE).[1d] As shown in Scheme 3, we proposed that the
photocatalytically generated radical cation I of the oxidizable
ynamide/pyridine N-oxide adduct could lead to a distonic cation
vinyl radical intermediate II(a) or II(b) via nucleophilic attack by
the oxygen of pyridine N-oxide. We predict that the site selective
generation of cationic vinyl radical II(a) would be favored due to
the resonance stabilization of phenyl group towards the vinyl
radical. Guided by recent photocatalyzed Minisci reactions[19] and
Miura along with Murakami’s study on the photocatalyzed ortho-
alkylation/cleavage reaction of pyridine N-oxides with alkenes,[20]
we predicted that an intramolecular Minisci-type pathway would
then afford the aminyl radical cation III. Alternatively, the direct
concerted reaction from I to III is also possible. Following
simultaneous or successive-stepped 1,2-electron shift, β-N-O
bond scission and proton transfer would be driven by
aromatization to deliver the resonance-stabilized radical IV from
III. The radical IV would undergo a second SET event with the
oxidized photo-system and a proton transfer to regenerate the
Results and Discussion
Our inquiry began with the voltammetry measurements of a
ynecarbamate1a/pyridine N-oxide system (Figure 1). The
acetonitrile solution of mixed 1a and 2a (1a:2a = 1:1) exhibits an
oxidation onset near 1.32 V vs SCE, which is significantly lower
than the observed irreversible oxidation for 1a at E1/2ox = 1.75 vs
SCE (oxidation onset at 1.62 V). We rationalize that this reduced
milder oxidation onset can be attributed to the formation of an
ynamide/pyridine N-oxide oxidizable adduct; while the labile non-
covalent electrostatic interaction between ynamide and pyridine
N-oxide results in the unapparent oxidation potential for the
adduct. We are aware of the possibility that the oxidizable adduct
could be an electron donor–acceptor (EDA) complex[17] of
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
photocatalyst ground-state and furnish α-(2-pyridinyl) benzyl
amide product 3a. In this proposed transformation, pyridine N-
oxide not only serves as a redox auxiliary to enable the
challenging photocatalyzed single-electron oxidation process, but
also functions as an oxygen transfer agent and a trap of the highly
reactive vinyl radical intermediate to suppress the undesired
dimerization and further oxidation.
MeClO4 (entry 10), and only unreacted 1a was recovered without
any detectable transformation. Although there is no reported
study and evidence indicating the feasibility of a 1,3-dipolar
cycloaddition of pyridine N-oxide and disubstituted ynamide
possessing internal triple bond, we recognize that 3a might be
generated from the speculate cycloaddition product through an N-
O bond cleavage process. To address this possible alternative,
the examination of Lewis acid catalysts, including Cu(OTf)2,
Yb(OTf)3, and Zn(OTf)2, were examined (entry 11, and Table S1).
Except for recovery of 1a, neither desired product 3a, nor the
cycloaddition product was detected. While we cannot definitively
rule out the 1,3-dipolar cycloaddition pathway, we favor
theproposed photocatalytic pathway (Scheme 3) based on the
aforementioned results and latter mechanism studies.
Ph
(PC)
Ph
photocatalysis
O
+
N
N
O
N
O
hv
O
N
O
O
1a
3a
2a
Ph
N
Ph
SET
N
N
H
+
PC
H
O
O
N
PC
O
O
IV
hv
O
O
O
Table 1. Exploration of Reaction Conditions.
O
*
Ph
N
PC
SET
photocatalyst
(5 mol%)
N
O
O
Ph
O
O
O
N
oxidizable adduct
N
O
H
+
O
N
N
O
Ph
N
Ph
CH3CN, blue LEDs
rt, 16 h
N
O
N
O
O
O
Ph
,
N
Me
ClO4
Me
O
N
2a
1a
1.2 equiv
favored
3a
II(a),
Ph
-
O
O
III
Cl-
N
O
O
N
Me
Ph
I
Me2N
NMe2
S
N
N
N
Me
Mes-Acr-MeClO4
O
O
methylene blue
disfavored
II(b),
Entry
1
2
3
4
5
6
7
8
variation from the standard conditions[a]
methylene blue
Mes-Acr-MeClO4
no light
no photocatalyst
no photocatalyst at 80 °C for 2 days[c]
sunlight and 6 days[c]
DCM instead of CH3CN[c]
DCE instead of CH3CN[c]
MeOH instead of CH3CN[c]
pyridine instead of pyridine N-oxide[c]
Cu(OTf)2 instead of photocatalyst
yield[b] (%)
Scheme 3. Proposed mechanism. SET = single-electron transfer.
49
87
<5
<5
<5
48
58
64
8
Our examination of the proposed ortho-alkylation reaction
began with methylene blue (5 mol%) catalyzed reaction of 1a and
pyridine N-oxide 2a with blue LED light irradiation (34 W, λmax
=
450 nm, ∼400−520 nm) at room temperature (Table 1, entry 1).
As proposed, the desired product 3a was generated smoothly in
49% yield with excellent site selectivity for the triple bond (> 20:1).
The use of 9-mesityl-10-phenyl acridinium perchlorate (Mes-Acr-
MeClO4) could improve the yield of 3a to 87% (entry 2), which is
identified as the optimized condition. Neither ruthenium
([Ru(bpy)3][PF6]2, [Ru(bpz)3][PF6]2), nor iridium photocatalysts
(Ir[dF(CF3)ppy]2(dtbbpy)PF6) were effective catalysts for this
transformation (Table S1). Only unconverted starting materials
were recovered when the mixture was heated at 80°C for three
days without the photocatalyst or photoirradiation (Table 1,
entries 3 to 5). Noteworthy, the product 3a was formed in 48%
yield under sunlight irradiation however with longer reaction time
(entry 6). Solvent screening was also performed (entries 7 to 9,
Table S1). The use of aprotic solvent dichloromethane and 1,2-
dichloroethane (entries 7 and 8) also delivered the formation of
3a in moderate yields. However, when methanol was employed
as the solvent (entry 9), the reaction was significantly suppressed.
Such results support the proposed pre-association of ynamide
and pyridine N-oxide which is favored in aprotic solvents, while
the use of protic solvent weakens the non-covalent
interactions.[11,17] Instead of using pyridine N-oxide, the reaction
of pyridine and 1a was performed in the presence of Mes-Acr-
9
10
11
<5
<5
[a] Reaction conditions: 1a (0.20 mmol, 1.0 equiv.) 2 (0.24 mmol, 1.2 equiv.),
and 5mol% of photocatalyst were dissolved in dry CH3CN (2.0 ml) under
blue LED lamps (∼400−520 nm, λmax = 450 nm, 34 W, more information at
Kessil.com) for 16 h. [b] Yield of isolated product 3a based on the limiting
reagent 1a. [c] Mes-Acr-MeClO4 was applied as photocatalyst. CH3CN =
acetonitrile, DCM = dichloromethane, DCE = 1,2-dichloroethane.
With the optimized conditions, substrate generality was
investigated for the photocatalyzed ortho-alkylation of various
heteroaromatic N-oxides and ynamides (Table 2). Those with
ortho, meta, or para alkyl and halogen substituents on the pyridine
N-oxide reacted smoothly with 1a, generating the corresponding
products in good yields (77−93%, 3a-3e) with excellent site
selectivities. The reactions of pyridine N-oxides with para
electron-withdrawing substituents furnished products 3f and 3g
with lower yields. The scope with respect to ynecarbamates with
various aryl substituents was examined in the reactions of 2-
methylpyridine N-oxide (2b), affording the corresponding
products (3h to 3l). Structure of product 3j was identified
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
spectroscopically and confirmed by X-ray diffraction analysis.[21]
N-Oxide of quinoline was also compatible with this transformation
(3m, 72%). In addition to ynecarbamates, ynesulfonamides were
ideal reagents as well, yielding products 3n and 3o with high yield.
The reaction was further tested with alkyl substituted ynamides.
Notably, employment of hexyl substituted ynamide completely
switched the site selectivity of the triple bond to preferentially
producing 3p albeit with a lower isolated yield. We rationalize that
the grater resonance-stabilization that occurs in the oxazolidinone
group towards the proposed distonic cation vinyl radical
intermediate II(c) may account for the switched site selectivity,
when compared to the alkyl group. When cyclopropyl substituted
ynamide was subjected to the reaction, 3qa with switched site
selectivity was also isolated as the major product. While 3qb with
carbonyl group adjacent to the oxazolidinone group was also
obtained with 15% yield. No three-member ring-opening product
is observed. We suspected that the ortho-addition of the highly
reactive vinyl radical to the pyridinium ring is faster than the ring-
opening and radical migration process.[22]
To further extend the reaction scope and the compatibility
of the proposed alkyne activation strategy by applying pyridine
N-oxide as a redox auxililary, the reactions of arylacetylenes
and pyridine N-oxides were then explored (Table 3). A
voltammetry measurement of the diphenylacetylene/pyridine
N-oxide system was also carried out (Figure S3). Notably, a
weak
irreversible
oxidation
potential
for
the
diphenylacetylene/pyridine N-oxide system was detected at
ox
E1/2 = 1.52 vs SCE, as well with an observable oxidation
onset near 1.4 V vs SCE, that is significantly lower than the
ox
oxidation protentional of diphenylacetylene (E1/2 = 1.85 vs
SCE).[23] We postulated that
a possible π-π interaction
between pyridine N-oxide and arylacetylene may deliver the
formation of an oxidizable adduct. Pyridine N-oxides
possessing methyl, chloro, or ester substituents were suitable
substrates, affording the α-(2-pyridinyl) benzyl ketone products
in good yields (5a to 5e) at a prolonged reaction time (24 h).
Bis(4-bromophenyl)acetylene also reacted smoothly with 2a
generating product 5f with moderate yield. However, when
phenylacetylene, 1-phenyl-1-propyne or diphenylpropynone
was employed in the reaction with 2a, only 2-benzoylpyridine
6 was obtained with low yield, which may be formed through
further oxidation of radical intermediate IV’ with involvement of
another pyridine N-oxide as oxygen transfer agent. When 1-
Table 2. Scope of ynamides and pyridine N-oxides.[a]
R1 EWG
(5 mol%)
EWG
Mes-Acr-MeClO4
R
N
R1
N
R2
R2
chloro-4-(phenylethynyl)benzene
was
applied,
the
+
N
R
CH3CN, blue LEDs
rt, 16 h
N
O
regioisomers 5g and 5h (5g : 5h = 1.2 : 1) were both obtained
with combined 72% yield.
O
2
1
3
, R = H, 87%
, R = 6-Me, 93%
3a
3b
Ph
, R = 6-Cl, 86%
, R = 3-Me, 77%
, R = 4-Me, 82%
3c
3d
Table 3. Scope of arylacetylenes.[a]
O
N
3j
R
3e
3f
O
N
O
R1
, R = 4-CO
(5 mol%)
2Me, 61%
R2
Mes-Acr-MeClO4
R
, R = 4-NO , 49%
R1
R2
+
3g
2
N
R
CH3CN, blue LEDs
rt, 24 h
N
O
O
2
R
5
4
, R = 4-Cl, 81%
, R = 3-Cl, 87%
, R = 2-Cl, 83%
, R = 4-OMe, 83%
Ph
3h
3i
3j
3k
3l
O
N
O
N
Ph
Ph
O
N
O
Ph
O
N
O
, R = 4-CN, 52%
Ph
72%
3m,
+
NH
O
CH3
Cl-
N
O
.
O
CH3
5b HClc
Ph Me
N
, 82%
, 88%b
Ph
5a
O
N
R
Ph
Ph
CH3
, R = Ms, 92%
, R = Ts, 88%
(CH2)5
3n
3o
N
O
Ph
Ph
MeO2C
H3C
Ph
N
O
CH3
N
N
O
O
N
O
, 48%
CH3 3p
O
, 68%
Cl
N
, 86%
5d
, 85%
Ar
5e
5c
O
N
= Ph, R2 = CH
, 24% of
R1
6
O
3
N
Ar
= Ph, R2 = H, 18% of
R1
R1
6
Ph
O
:
= 3:1
N
O
= Ph, R2 = COPh, 28% of
N
O
N
O
3qa 3qb
6
O
, 15%
6
, 46%
CH3
3qb
CH3
CH3 3qa
IV'
Ar = 6-BrC6H4
5f
Ph
, 69%
N
N
O
O
R2
O
II(c)
Alkyl
Ar1
favored by grater resonance-
stabilization of oxazolidinone
= Ph, Ar2 = 4-ClC
, Ar1
Ar2
5g
5h
H4
=6Ph
N
= 4-ClC
, Ar1
:
,
6H4 Ar2
= 1.2:1, 72% combined yield
N
O
5g 5h
O
CH3
[a] For experimental details, see supporting information.
[a] For experimental details, see supporting information.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
To gain mechanistic insight into this transformation, radical
inhibition and tapping experiments were conducted (Scheme 4,
Scheme S1-S3). Upon the addition of the radical scavenger
2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or butylated
hydroxytoluene (BHT), the alkylation reaction was substantially
suppressed (Scheme 4a, S2). α-Keto imide 7 was isolated in 14%
yield from the reaction of 1a, 2a, and TEMPO (Scheme 4a). While
only unconverted 1a was recovered from the reaction of ynamide
1a and TEMPO under the standard condition without formation of
7 (Scheme 4b). These experiments not only suggest the
involvement of radical intermediates in this transformation, but
also indicate the indispensability of pyridine N-oxide for
photocatalytic single-electron oxidation of alkynes. Furthermore,
CCl4 was employed to trap the reactive radical species (Scheme
4c). In the presence of CCl4 (2 equiv), the α-chloro imide 8 was
isolated in 13% yield along with the desired product 3b in 38%
yield. Noteworthy, the chlorinated intermediate 9 was successfully
detected by ESI-MS analysis of the reaction mixture, which
accounts for the generation of 8. These results clearly point to the
involvement of a distonic cation vinyl radical intermediate II’,
which is consistent with our mechanistic proposal (Scheme 3).
photocatalyzed single-electron oxidation of alkyne process
cannot be ruled out, taken together with the electrochemical study
(Figure 1) and radical quenching experiments (Scheme 4b), the
function of pyridine N-oxide as a redox auxiliary to facilitate single-
electron oxidation of carbon-carbon triple bonds is operative and
indispensabile.
A. Addition of radical inhibitors
O
Mes-Acr-MeClO4
(5 mol%)
O
O
, < 5%
+
+
+
3a
1a
2a
TEMPO
N
(a)
Ph
CH3CN, blue LEDs
rt, 16 h
2.0 equiv.
,
O
7
14%
Mes-Acr-MeClO4
(5 mol%)
, < 5%
TEMPO
+
7
1a
(b)
CH3CN, blue LEDs
rt, 16 h
2.0 equiv.
B. Trap of intermediates
O
Mes-Acr-MeClO4
(5 mol%)
O
N
, 38%
,
3b
Ph
(c)
+
+
+
1a
CCl4
O
H
3C
N
7
9%
CH3CN, blue LEDs
rt, 8 h
Cl
, 13%
2.0 equiv.
2b O
8
via
H
3C
N
O
H
CCl4
N
O
3C
Cl
Ph
Ph
, MS
= 331.1
N
N
9
O
O
Detected by ESI-MS
II'
O
O
Scheme 4. Mechanistic study.
Figure 2. a) Stern–Volmer emission quenching studies of ynamide 1a and
1a/pyridine N-oxide 2a system. b) Stern–Volmer emission quenching studies of
diphenylacetylene 4a and 4a/pyridine N-oxide 2a system. y = I0/I, x = KSV; error
<5% (estimated from multiple trials). Stern–Volmer equation: I0/I = 1 + Ksv[Q]; I0
and I are the fluorescence intensity in the absence and presence of quencher
Q, KSV is the Stern-Volmer constant, and [Q] is the concentration of quencher
alkyne.
We have sought to obtain further evidence for the proposed
alkyne activation stratergy by using pyridine N-oxide as a redox
auxililary. The Stern–Volmer fluorescence quenching studies of
alkyne alone and in combination with pyridine N-oxide using the
preferred Mes-Acr-MeClO4 photocatalyst were perfomed. As
revealed in Figure 2a, the emission quenching of the excited state
of the photocatalyst was significantly enhanced by the ynamide
1a/pyridine N-oxide 2a combination system (Ksv = 104.050),
compared to the solo 1a test (Ksv = 48.707). Similar observations
can also be noticed for the diphenylacetylene 4a/ pyridine N-oxide
2a system (Ksv = 92.836 vs Ksv = 41.247 for 4a alone). This finding
indicates that the addition of pyridine N-oxide promotes the
photocatalyzed oxidative process of alkynes. Although the direct
Based on our electrochemical study, radical trapping and
quenching experiments, and Stern–Volmer fluorescence
quenching studies, a general plausible mechanism of the
photocatalyzed ortho-alkylation of pyridine N-oxide with alkynes
is described in Scheme 5. Oxidized by the excited photocatalyst,
a cation radial intermediate I can be generated from the
alkyne/pyridine N-oxide adduct; alternatively, the catalytical
generation of alkyne cation radical is also possible. Both cation
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
radical intermediates could lead to the distonic cation vinyl radical
intermediate II via nucleophilic attack by the oxygen of pyridine N-
oxide. Following Minisci-type reaction leads to the aminyl
radical cation III. Subsequent 1,2-electron shift, β-N-O bond
scission, proton transfer, and SET event is driven by
aromatization to furnish α-(2-pyridinyl) functionalized carbonyl
product and achieve photocatalyst turnover.
transformation will provide a new strategy of greater value for
future applications in alkyne activation and organic synthesis via
vinyl radicals.
Acknowledgements
Support for this research from Westen Kentucky University and
the Chemistry Deparment is gratefully acknowledged. J.P.M.
thanks Graduate Student Research Grant from Westen Kentucky
University. The authors thank Pauline Norris at Advanced
Materials Institute at Westen Kentucky University for ESI-MS
analysis.
R1
R2
R1
R2
N
O
H
PC
+
PC
R1
R2
R1
I
N
O
N
N
O
R1
O
N
R2
O
R2
N
O
R1
R2
II
III
via
alkyne cation radical
Keywords: photocatalysis • alkyne • ynamide • pyridine N-oxide
Scheme 5. The general plausible mechanism of the photocatalyzed ortho-
alkylation of pyridine N-oxide with alkynes. PC = photocatalyst
• alkylation
[1]
[2]
[3]
[4]
For selected reviews, see: a) T. P. Yoon, M. A. Ischay, J. Du, Nat. Chem.
2010, 2, 527; b) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc.
Rev. 2011, 40, 102; c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
Chem. Rev. 2013, 113, 5322; d) N. A. Romero, D. A. Nicewicz, Chem.
Rev. 2016, 116, 10075; e) M. H. Shaw, J. Twilton, D. W. C. MacMillan,
J. Org. Chem. 2016, 81, 6898; f) M. D. Kärkäs, J. A. Porco, C. R. J.
Stephenson, Chem. Rev. 2016, 116, 9683.
Efforts devoted to exploring the synthetic practicability of
this photocatalyzed reaction demonstrated the ease of access to
a gram scale reaction [Eq. (1)]. Furthermore, treatment of 3b
under classic reduction conditions by sodium borohydride gave
the 2-(6-methylpyridin-2-yl)-2-phenylethanamine product 10 in
72% yield [Eq. (2)]. This photocatalyzed reaction of ynamides and
pyridine N-oxides along with the convenient reduction provide
access to the arylethylamine compounds, that are an important
skeleton in many natural products and bioactive compounds,
such as chlorphenamine and disopyramide.
For review see: a) K. A. Margrey, D. A. Nicewicz, Acc. Chem. Res. 2016,
49, 1997. For selected recent examples, see: b) X. Hu, G. Zhang, F. Bu,
A. Lei, ACS Catalysis 2017, 7, 1432; c) L. Wang, F. Wu, J. Chen, D. A.
Nicewicz, Y. Huang, Angew. Chem. Int. Ed. 2017, 56, 6896; Angew.
Chem. 2017, 129, 7000; d) F. Wu, L. Wang, J. Chen, D. A. Nicewicz, Y.
Huang, Angew. Chem. Int. Ed. 2018, 57, 2174; Angew. Chem. 2018, 130,
2196.
For selected recent examples, see: a) N. A. Romero, K. A. Margrey, N.
E. Tay, D. A. Nicewicz, Science 2015, 349, 1326; b) J. Jiao, K. Murakami,
K. Itami, ACS Catalysis 2016, 6, 610; c) X. Hu, G. Zhang, F. Bu, X. Luo,
K. Yi, H. Zhang, A. Lei, Chem. Sci. 2018, 9, 1521; d) J. B. McManus, D.
A. Nicewicz, J. Am. Chem. Soc. 2017, 139, 2880; e) N. E. S. Tay, D. A.
Nicewicz, J. Am. Chem. Soc. 2017, 139, 16100; f) L. Niu, H. Yi, S. Wang,
T. Liu, J. Liu, A. Lei, Nat. Commun. 2017, 8, 14226.
Ph
O
Mes-Acr-MeClO4
(5 mol%)
O
N
+
O
Ph
N
H
N
O
3C
O
N
O
CH3CN, blue LEDs
rt, 24 h
, 1.2 equiv
(1)
(2)
, 81%
3b
2.19 g
CH3
2b
, 1.87 g
1a
1.30 g
a) A. G. Davies, 17.5 Radical cations of alkynes. In Phosphorus-
Centered Radicals, Radicals Centered on Other Heteroatoms, Organic
Radical Ions. Part 2, (Ed.: H. Fischer), Springer Berlin Heidelberg: Berlin,
Heidelberg, 2009; pp 299-301; b) K. B. Yoon, Chem. Rev. 1993, 93, 321;
c) S. Shih, J. Catal. 1983, 79, 390.
NaBH4
Ph
O
Ph
(6.0 equiv)
H
3C
N
H
N
3C
MeOH
°
N
O
O
NH
, 72% yield
0
C, 2 h
2
10
3b
[5]
[6]
For the only reported catalytic oxidation of alkyne involving alkyne cation
radical, see: H.-T. Qin, X. Xu, F. Liu, ChemCatChem 2017, 9, 1409.
a) Appendix B: Tables of Physical Data. In Fundamentals and
Applications of Organic Electrochemistry. (Eds.: T. Fuchigami, S. Inagi,
M. Atobe) John Wiley & Sons, Ltd, 2015; b) H. G. Roth, N. A. Romero,
D. A. Nicewicz, Synlett 2016, 27, 714.
Conclusions
In summary, we have developed a facile and scalable
photocatalyzed ortho-alkylation of pyridine N-oxides with
ynamides and arylacetylenes.
[7]
a) J. L. Courtneidge, A. G. Davies, S. M. Tollerfield, J. Rideout, M. C. R.
Symons, J. Chem. Soc. Chem. Commun. 1985, 1092; b) M. Shiotani, K.
Ohta, Y. Nagata, J. Sohma, J. Am. Chem. Soc. 1985, 107, 2562; c) J. L.
Courtneidge, A. G. Davies, P. S. Gregory, J. Chem. Soc. Chem.
Commun. 1986, 1273; d) H. Tachikawa, M. Shiotani, K. Ohta, J. Phys.
Chem. 1992, 96, 164.
The protocol provides a
convenient access to a variety of α-pyridyl functionalized
carbonyls, alone with derivatized arylethylamine compounds.
Mechanistic insights, including electrochemical study, radical
inhibition and tapping experiments, and Stern–Volmer
fluorescence quenching studies, reveal that pyridine N-oxide
serves as a redox auxiliary in concert with ynamides and
arylacetylenes to affect a mild photocatalyzed single-electron
oxidation process of carbon-carbon triple bonds through a
distonic cation vinyl radical intermediate. We expect that this
[8]
[9]
V. V. Aleksander, Mini. Rev. Org. Chem. 2017, 14, 204.
a) K. C. Nicolaou, D. L. F. Gray, J. Tae, J. Am. Chem. Soc. 2004, 126,
613; b) W. Mahabusarakam, S. Deachathai, S. Phongpaichit, C.
Jansakul, W. C. Taylor, Phytochemistry 2004, 65, 1185; c) R. M.
Wadkins, J. L. Hyatt, X. Wei, K. J. P. Yoon, M. Wierdl, C. C. Edwards, C.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
L. Morton, J. C. Obenauer, K. Damodaran, P. Beroza, M. K. Danks, P.
M. Potter, J. Med. Chem. 2005, 48, 2906.
[16] a) Y. Wang, L. Zhang, Synthesis 2015, 47, 289; b) M. Łukomska, A. J.
Rybarczyk-Pirek, M. Jabłoński, M. Palusiak, Phys. Chem. Chem. Phys.
2015, 17, 16375; c) H.-S. Yeom, S. Shin, Acc. Chem. Res. 2014, 47, 966.
[17] For selected reviews, see: a) C. G. S. Lima, T. de M. Lima, M. Duarte, I.
D. Jurberg, M. W. Paixão, ACS Catalysis 2016, 6, 1389; b) S. V. Rosokha,
J. K. Kochi, Acc. Chem. Res. 2008, 41, 641.
[10] a) J. W. Beatty, J. J. Douglas, K. P. Cole, C. R. J. Stephenson, Nat.
Commun. 2015, 6, 7919; b) Joel W. Beatty, James J. Douglas, R. Miller,
Rory C. McAtee, Kevin P. Cole, Corey R. J. Stephenson, Chem 2016, 1,
456.
[11] a) S. Yamada, Chem. Rev. 2018, 118, 11353; b) B. L. Schottel, H. T.
Chifotides, K. R. Dunbar, Chem. Soc. Rev. 2008, 37, 68; c) I. Geronimo,
N. J. Singh, K. S. Kim, J. Chem. Theory Comput. 2011, 7, 825.
[12] a) G. Alachouzos, A. J. Frontier, Angew. Chem. Int. Ed. 2017, 56, 15030;
Angew. Chem. 2017, 129, 15226; b) G. Alachouzos, A. J. Frontier, J. Am.
Chem. Soc. 2019, 141, 118.
[18] P. A. Raffo, F. D. Cukiernik, R. F. Baggio, Acta Cryst. C. 2015, 71, 84.
[19] For selected examples, see: a) J. Jin, D. W. C. MacMillan, Nature 2015,
525, 87; b) J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2015, 54,
1565; Angew. Chem. 2015, 127, 1585; c) J. Dong, X. Lyu, Z. Wang, X.
Wang, H. Song, Y. Liu, Q. Wang, Chem. Sci. 2019, 10, 976.
[20] W. Zhou, T. Miura, M. Murakami, Angew. Chem. Int. Ed. 2018, 57, 5139;
Angew. Chem. 2018, 130, 5233.
[13] a) X. Chen, S. A. Ruider, R. W. Hartmann, L. González, N. Maulide,
Angew. Chem. Int. Ed. 2016, 55, 15424; Angew. Chem. 2016, 128,
15650; b) A. Darù, D. Roca-López, T. Tejero, P. Merino, J. Org. Chem.
2016, 81, 673.
[21] CCDC 1894226 (3j) and 1894227 (5b·HCl) contain the supplementary
crystallographic data for this paper.
[22] For selected examples, see: a) M. Hu, R.-J. Song, J.-H. Li, Angew. Chem.
Int. Ed. 2015, 54, 608; Angew. Chem. 2015, 127, 618; b) J. Zhang, S.
Cheng, Z. Cai, P. Liu, P. Sun, J. Org. Chem. 2018, 83, 9344; c) X. Zhu,
W. Deng, M.-F. Chiou, C. Ye, W. Jian, Y. Zeng, Y. Jiao, L. Ge, Y. Li, X.
Zhang, H. Bao, J. Am. Chem. Soc. 2019, 141, 548.
[14] For selected reviews, see: a) K. A. DeKorver, H. Li, A. G. Lohse, R.
Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064; b)
G. Evano, A. Coste, K. Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840;
Angew. Chem. 2010, 122, 2902; c) X.-N. Wang, H.-S. Yeom, L.-C. Fang,
S. He, Z.-X. Ma, B. L. Kedrowski, R. P. Hsung, Acc. Chem. Res. 2014,
47, 560.
[23] H. G. Roth, N. A. Romero, D. A. Nicewicz, Synlett 2016, 27, 714.
[15] Wang, R. L.; Buhrmester, C.; Dahn, J. R. J. Electrochem. Soc. 2006, 153,
A445.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901065
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
R1 EWG
EWG
Jonathan P. Markham, Ban Wang,
Edwin D. Stevens, Stuart C. Burris and
Yongming Deng*
R1
N
R2
N
R2
R
R
N
N
O
R
23 examples
up to 93% yield
photocatalyst
Ar
N
O
, rt
Blue LEDs
Page No. – Page No.
Ar
redox auxiliary
and reactant
O
ortho-Alkylation of Pyridine N-oxides
with Alkynes by Photocatalysis:
Pyridine N-oxide as Redox Auxiliary
Ar
Ar
Pyridine N-oxide as a redox auxiliary for alkynes: A ortho-alkylation of pyridine N-
oxide with alkynes, including ynamides and arylacetylenes, has been achieved by
organic photocatalysis, providing access to a series of α-(2-pyridinyl) benzyl
carbonyl compounds. Pyridine N-oxide function as both a redox auxiliary and
radical acceptor to achieve the challenge photocatalytic single-electron oxidation of
carbon-carbon triple bond.
This article is protected by copyright. All rights reserved.