Photoinduced Divergent Alkylation/Acylation of Pyridine N-Oxides with Alkynes under Anaerobic and Aerobic Conditions

Article abstract of DOI:10.1021/acs.orglett.9b01940

Ortho-alkylated and ortho-acylated pyridines have been conveniently synthesized from pyridine N-oxides and alkynes under visible-light-mediation in a metal-free manner. The alkynes served as both alkylating and acylating agents via switching between anaerobic and aerobic conditions. The overall strategy accommodates a broad scope of substituted pyridine N-oxides and alkynes, with excellent regioselectivity in a number of cases.

Full text of DOI:10.1021/acs.orglett.9b01940

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoinduced Divergent Alkylation/Acylation of Pyridine N‑Oxides
with Alkynes under Anaerobic and Aerobic Conditions
Jin-hui Xu,† Wen-bin Wu,† and Jie Wu*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore, Republic of Singapore
S
* Supporting Information
ABSTRACT: Ortho-alkylated and ortho-acylated pyridines have been conveniently synthesized from pyridine N-oxides and
alkynes under visible-light-mediation in a metal-free manner. The alkynes served as both alkylating and acylating agents via
switching between anaerobic and aerobic conditions. The overall strategy accommodates a broad scope of substituted pyridine
N-oxides and alkynes, with excellent regioselectivity in a number of cases.
Scheme 1. Functionalization of Pyridine/Quinoline N-
Oxides with Alkynes
ynthesizing pyridine derivatives is of vital importance in
Sorganic and medicinal chemistry because pyridines are
privileged structural motifs in natural products1 and
pharmaceutical agents.2 In this context, transition-metal-
catalyzed3 or radical-mediated4 direct C−H functionalization
of pyridines has emerged as an efficient and atom-economical
strategy to access this important family of heterocyclic
compounds. However, low selectivity is normally a problem
in those types of transformations. Compared with pyridines,
pyridine N-oxides are readily available and are ideal alternatives
for the preparation of pyridine derivatives with improved
regioselectivity owing to their unique character.
Alkynes are versatile reactants in the selective functionaliza-
tion of pyridine N-oxides (Scheme 1). Nucleophilic reaction of
pyridine N-oxides with terminal alkynes in the presence of a
base5 delivered ortho-alkynylated pyridine N-oxides (Scheme
1a). The groups of Hiyama6 and Matsuo7 reported respectively
alkenylation of pyridine N-oxides at the C-2 position and
quinoline N-oxides at the C-8 position by transition-metal-
catalyzed reactions (Scheme 1b). At 200 °C with microwave
irradiation, Maulide et al. successfully realized the generation
of meta-substituted pyridines to access metyrapone analogs
using pyridine N-oxides and electron-deficient alkynes
(Scheme 1c).8 Quinoline N-oxides were found to undergo
cobalt(III) or rhodium(III)-catalyzed coupling with alkynes to
provide C-8 functionalized quinolines (Scheme 1d).9 The N-
oxide acted as a directing group to induce the C-8
functionalization of quinolines as well as a source of the
oxygen atom in these transformations. In 2018, Singh et al.
reported oxidative acylation of electron-deficient heteroarenes
including pyridine N-oxides and quinolone N-oxides using
terminal alkynes in the presence of a silver catalyst and excess
potassium persulfate, K2S2O8 (Scheme 1e).10 Even though
significant progress has been achieved, selective C-2 alkylation
and acylation of pyridine N-oxides, especially in metal-free
conditions, are still challenging and highly desirable.
Visible-light-mediated photocatalysis has witnessed dramatic
developments over the past decade, which has enabled
previously unknown transformations.11 Alkylation of pyridine
N-oxides, induced by visible light, has been realized using
alkenes and alkyltrifluoroborate potassium salts as alkylation
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01940
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reagents (Schemes 2a,b).12 As part of our continuing efforts in
the Supporting Information). In contrast, acids such as
trifluoroacetic acid (TFA), trifluoromethanesulfonic acid
(TfOH), and HBF4, improved the reaction yield dramatically
(entries 4−9). Nearly quantitative yields could be obtained
with 20 mol% HBF4 at 50 °C (entry 7). Further optimization
showed that hexafluoroisopropanol (HFIP) could be employed
to replace strong acidic additives to tolerate acid-labile
functionalities, also with excellent yields (entry 10). As the
solvent, acetone, which is greener and less costly than MeCN,
was equally effective (entries 11 and 12). No product was
obtained in the absence of either photocatalyst or light,
demonstrating the need for all these components (see the
Supporting Information).
development of visible-light-promoted green synthesis,13 we
Scheme 2. Photoinitiated Functionalization of Pyridine N-
Oxides
We then investigated the reaction scope of alkylation of
pyridine N-oxides under the optimal conditions (Table 1, entry
12). As depicted in Scheme 3a, with n-dec-5-yne as a
Scheme 3. Substrate Scope of Alkylation of Pyridine N-
Oxides with Alkynes
report herein a metal-free photoinduced divergent alkylation/
acylation of pyridine N-oxides using alkynes as the alkylation
and acylation reagents under anaerobic or aerobic conditions
(Schemes 2c,d).
We initiated the study by alkylation of pyridine N-oxide (1a)
with n-dec-5-yne (2a) in MeCN in the presence of the
photocatalyst 9-mesityl-10-methylacridinium perchlorate
(Mes-Acr+ClO4 ) under blue LED irradiation (Table 1).
−
This led to the desired alkylated product (3a) which was
obtained in 44% yield (entry 1), along with pyridine
byproducts. The transformation was sensitive to pH. Addition
of 0.5 or 1.0 equiv of pyridine resulted in a substantial decrease
in yield (entries 2 and 3). Other bases, such as NaHCO3,
NaOAc, and K3PO4, showed similar detrimental effects (see
Table 1. Exploration of Optimal Conditions for Alkylation
a
entry
additives (X mol%)
T (°C)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
−
rt
rt
rt
rt
50
50
50
50
50
50
50
50
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
acetone
acetone
44
26
15
62
80
92
>99
76
92
pyridine (50)
pyridine (100)
aq. HBF4 (50)
aq. HBF4 (5)
aq. HBF4 (10)
aq. HBF4 (20)
TFA (20)
TfOH (20)
HFIP (100)
aq. HBF4 (20)
HFIP (100)
b
a
b
Isolated yields. Ratios of regioisomers based on analysis of the
b
c
d
1
crude H NMR spectra. Ratios of keto/enol. Isolated yields at 6
mmol scale.
b
b
representative alkyne partner, a diverse range of substituted
pyridine N-oxides provided alkylation products in good to
excellent yields. Ortho- or para-substituents pyridine N-oxides
underwent C-2 alkylation with excellent regioselectivity (3a−
3i, 3l−3o), while mono meta-substituted pyridine N-oxides
delivered a mixture of products (3j, 3k). The reaction tolerated
many functional groups, such as halogens, nitriles, nitro
compounds, and carboxylic acids. In addition, quinoxaline N-
10
11
12
>99
>99
>99 (92)
b
c
a
Yields based on analysis of the crude 1H NMR spectra using CH2Br2
as an internal standard. Aq. HBF4 (8.0 M in water) was applied.
The number in parentheses refers to isolated yield; rt = room
temperature.
b
c
B
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Letter
oxide and 2,2′-dipyridyl N-oxide could also be utilized to
prepare the alkylated products (3q, 3r) in good yield.
Scheme 5. Scope of Acylation of Pyridine N-Oxides with
Alkynes
A remarkably broad scope of alkynes, including symmetrical,
unsymmetrical, and terminal alkynes, were effective under the
optimal conditions and provided ortho-substituted pyridine N-
oxides in moderate to good yields with generally excellent
regioselectivity (Scheme 3b). Electron-deficient (e.g., 4d, 4i,
4n) and electron-rich arenes (e.g., 4c, 4j, 4l), naphthalene
arenes (4o), and heteroarenes such as thiophene (4h, 4p, 4q)
were all well-tolerated. Most intriguing is the excellent
selectivity achieved with unsymmetrical and terminal alkynes.
Only one regioisomer, with aryl substituents located on the
pyridine side, was generated with aryl alkyl disubstituted
alkynes (4e−4g) and terminal alkynes (4k−4q). Notably,
when aryl heteroaryl disubstituted alkynes were used, a single
regioisomer (4h) was obtained in which the phenyl substituent
was located at the opposite site of the pyridine moiety.14
Changing the heteroaryl substituent to an aryl group led to a
mixture of regioisomers (4i). However, a single isomer (4j)
could still be obtained from the disubstituted alkyne bearing
aryl substituents with a distinct difference in electron densities.
Keto−enol tautomerization was observed in most of the
products due to the intramolecular hydrogen bonding between
the pyridine substituent and enol proton. In particular, the
products generated from pyridine N-oxides and terminal
alkynes were exclusively in the enol form (4k−4q).
a
b
Isolated products. Reaction conditions: under N2 for 24 h, then
c
under air for another 12 h. Isolated yields at 6 mmol scale.
conditions to obtain ortho acylated pyridine derivatives (5m,
6a−6f) in moderate yields (30−60%).
A series of control experiments were performed to gain
further insight into the nature of the alkylation and acylation
reactions. A significantly lower yield of the alkylation product
(3a) was obtained in the presence of 1 equiv of 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO), indicating a radical
process (Scheme 6a). Notably, the formation of peroxide 7 was
Compared with alkylation, acylation of pyridines has seen
only limited development and only a few examples have been
reported.10,15 During the optimization of the alkylation, we
found that ortho-acylated pyridines could be obtained in good
yields with the same starting materials simply by switching the
anaerobic conditions to aerobic (Scheme 4).
Scheme 6. Control Experiments for Elucidation of the
Mechanism
Scheme 4. Photoinduced Alkylation and Acylation of
Pyridine N-Oxides
Under the aerobic conditions, use of 20 mol% HBF4 and
MeCN as the solvent gave products in slightly better yields
compared to 100 mol% HFIP and acetone as the solvent, and
the scope for acylation was subsequently evaluated. As
illustrated in Scheme 5, with symmetric dialkyl alkynes,
acylated pyridine products (5a−5l) were obtained smoothly
in 35−75% yields16 across a wide range of functional groups,
including halogens, nitriles, nitro groups, and carboxylic acids.
However, when diphenylethyne was used as the acylation
reagent, the desired products were achieved in very low yields
due to the oxidation of diphenylethyne under the photoredox
conditions in the presence of O2 (see the Supporting
Information). To minimize the unwanted oxidation, acylation
using diphenylethyne was first conducted under a N2
atmosphere for 24 h and then in the presence of air for
another 12 h. In this way, the acylated pyridines (5m−5w)
were successfully obtained in 40%−70% yields. Finally,
terminal alkynes could be directly applied under aerobic
detected by ESI-MS, suggesting that pyridine N-oxide radicals
might be involved. Stern−Volmer fluorescence quenching
studies showed that light-activated photocatalyst Mes-Acr+*
(E1/2red* = +2.06 V vs SCE in MeCN) was quenched by
pyridine N-oxide (Ep/2 = +1.75 V vs SCE in MeCN) rather
than by the n-dec-5-yne (Ep/2 = +2.96 V vs SCE in MeCN,
C
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Scheme 6b and c).17 It was expected that the acylation product
(5) might be produced through a cascade reaction via
compound 3.18 Indeed, when 3a was subjected to the optimal
aerobic acylation conditions, 5a was obtained in 80% yield,
along with the pentanoic acid byproduct (Scheme 6d).
However, less than 5% yield of 5a was generated in the
absence of the photocatalyst. The fluorescence quenching
study demonstrated a strong quenching effect by O2 of light-
activated Mes-Acr+*, while 3a showed no quenching effect
(Figures S6, S7). However, only a moderate decrease in the
yield was detected in the presence of excess hydroquinone, a
radical quencher. This indicated that the transformation might
not involve radical species. Addition of the singlet oxygen
quencher 1,4-diazabicyclo[2.2.2]octane (DABCO) totally sup-
pressed the reaction (Scheme 6e), suggesting that a singlet
oxygen pathway played a major role in the formation of
acylation products.19
product will be further oxidized by singlet oxygen, produced
from energy transfer between the light-excited photocatalyst
3
and O2. The acylation product 6 will be accomplished via a
C−C bond cleavage of the intermediate VIII.20
In conclusion, we have developed a photoinduced
alkylation/acylation of pyridine N-oxides to synthesize a
variety of pyridine derivatives with alkynes as alkylating or
acylating agents switching between anaerobic and aerobic
conditions. Addition of acidic additives is important to achieve
products in high yields. These protocols exhibit a broad scope
across a range of pyridine N-oxides and alkynes, and are
distinguished by their metal-free character and excellent
regioselectivity achieved in a number of cases.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01940.
A plausible mechanism was proposed in light of all the
experimental data as shown in Scheme 7. As suggested by the
Detailed experimental procedures, characterization data,
Scheme 7. Plausible Mechanism for Alkylation and
Acylation
1
and H NMR and 13C NMR spectra of final products
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chmjie@nus.edu.sg.
ORCID
Jie Wu: 0000-0002-9865-180X
Author Contributions
†J.-H.X. and W.-B.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support provided by the
National University of Singapore and the Ministry of
Education of Singapore (MOE2017-T2-2-081), GSK-EDB
(R-143-000-687-592), and National Natural Science Founda-
tion of China (Grant No. 21702142, 21871205).
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