Catalyst-Free N-Deoxygenation by Photoexcitation of Hantzsch Ester

Article abstract of DOI:10.1021/acs.orglett.9b04632

A mild and operationally simple protocol for the deoxygenation of a variety of heteroaryl N-oxides and nitroarenes has been developed. A mixture of substrate and Hantzsch ester is proposed to result in an electron donor-acceptor complex, which upon blue-light irradiation undergoes photoinduced electron transfer between the two reactants to afford the products. N-oxide deoxygenation is demonstrated with 22 examples of functionally diverse substrates, and the chemoselective reduction of nitroarenes to the corresponding hydroxylamines is also shown.

Full text of DOI:10.1021/acs.orglett.9b04632

pubs.acs.org/OrgLett
Letter
Catalyst-Free N‑Deoxygenation by Photoexcitation of Hantzsch
Ester
Mikhail O. Konev,* Luana Cardinale, and Axel Jacobi von Wangelin*
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ABSTRACT: A mild and operationally simple protocol for the
deoxygenation of a variety of heteroaryl N-oxides and nitroarenes
has been developed. A mixture of substrate and Hantzsch ester is
proposed to result in an electron donor−acceptor complex, which
upon blue-light irradiation undergoes photoinduced electron
transfer between the two reactants to afford the products. N-
oxide deoxygenation is demonstrated with 22 examples of
functionally diverse substrates, and the chemoselective reduction
of nitroarenes to the corresponding hydroxylamines is also shown.
+0.79 V vs SCE in DMF) and has been used to initiate
reductive quenching cycles of photocatalysts or as a terminal
hydrogen atom source.9 More recently, 4-alkyl-substituted
derivatives were shown to behave in a similar manner, by
serving as alkyl radical precursors. Nishibayashi pioneered the
use of these systems, wherein the single-electron oxidation of
4-alkyl Hantzsch esters facilitates the expulsion of an alkyl
radical by aromatization-driven fragmentation. The resulting
radicals can then engage in C−C bond-forming reactions with
electron-deficient cyanoarenes.10 Building upon this platform,
a plethora of related reactions for the coupling of various
radical species via photoredox catalysis have been reported
(Scheme 1, bottom).11
antzsch esters, versatile reagents in the fields of synthetic
Hchemistry and reaction development, have only recently
become part of the rapidly growing collection of literature on
photomediated reaction platforms.1 Whereas their ground-
state reactivity has been investigated for the better part of a
century,2 Hantzsch esters have traditionally been used as
hydride donors, playing the role of NADH analogues for
transfer hydrogenation reactions,3,4 alkyl-group transfer,5 and
related reactions under thermal and oxidative conditions
(Scheme 1, top).6,7 In recent years, the chemistry of these
1,4-dihydropyridine derivatives has expanded to photomedi-
ated transformations, likely as a result of the increased interest
in photoredox catalysis.8 Hantzsch ester behaves as a
In addition to the modes of reactivity mentioned above, the
excitation of Hantzsch ester with visible light results in a highly
potent single-electron reductant (Eox = −2.28 V vs SCE in
DMF).12 Whereas this reactivity was first reported in the late
1970s,13 only recently was it applied in the context of synthetic
organic chemistry.14 Furthermore, 1,4-dihydropyridine deriva-
tives have also been employed in the rapidly developing field of
electron donor−acceptor (EDA) complex photochemistry.15
For example, several recent reports have demonstrated the
capability of Hantzsch ester to facilitate the cleavage of redox-
active auxiliaries and its propensity to promote reductive
fragmentation (Scheme 1, middle).16 To this end, we set forth
to examine the feasibility of this strongly reducing excited-state
intermediate for the deoxygenation of pyridine N-oxides to
pyridines, a ubiquitous moiety in organic chemistry.17
competent single-electron donor in the ground state (Eox
=
Scheme 1. Use of Hantzsch Esters in Organic Synthesis
Received: December 24, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04632
© XXXX American Chemical Society
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A

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Whereas several visible-light-mediated procedures for the
deoxygenation of pyridine N-oxides and their derivatives have
been developed,18 certain limitations are evident. These
protocols tend to rely on the use of a large excess of sacrificial
electron donors (from 5 equiv to solvent quantities) to
generate the reducing photocatalyst under inert conditions.
Furthermore, the necessity of expensive photocatalysts addi-
tionally discourages the use of these reactions. To address
these shortcomings, we sought the use of photoexcited
Hantzsch ester to perform the desired reduction using an
operationally simple setup.
Scheme 2. Substrate Scope for the Photoreduction of
Heteroaryl N-Oxides
e
We began our investigation using 4-phenylpyridine N-oxide
2 as the model substrate. Upon the irradiation of a mixture of
the N-oxide and Hantzsch ester in acetonitrile, we observed
significant product formation (Table 1, entry 2). Optimization
Table 1. Evaluation of Reaction Conditions
entry
variation from standard conditions
none
MeCN as solvent
DMSO as solvent
DMF as solvent
1.0 equiv 1
without 1
run in dark at 35 °C
run in dark at 65 °C
sparged with N2 for 5 min
410 nm irradiation instead of 448 nm
yield (%)
1
2
3
4
5
6
7
8
9
10
86
41
65
80
82
0
17
45
94
b
97
a
Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as an
b
external standard. Run on a 0.10 mmol scale. Reaction run for 6 h on
a 0.30 mmol scale.
a
b
Reaction run in DMSO as solvent. Reaction run in DMF as solvent.
c
d
Reaction run with 2.4 equiv of 1. Reaction run on a 1.0 mmol scale.
e
1
Reactions on 0.30 mmol scale. Yields in parentheses are H NMR
yields using 1,3,5-trimethoxybenzene as an external standard.
began with the investigation of a variety of solvents.
Dichloromethane (DCM) and dimethylformamide (DMF)
were found to be the top performers (entries 1 and 4), leading
to nearly complete conversion in 16 h. Because of its
convenience, DCM was the preferred choice for most cases
going forward. Whereas a 1:1 ratio of N-oxide to Hantzsch
ester was sufficient to afford good yields of product (entry 5), a
slight excess of reductant was used to facilitate shorter reaction
times. Control reactions were performed and confirmed that
blue-light irradiation is essential for efficient reduction to occur
(entries 7 and 8).19 Furthermore, the presence of oxygen only
marginally compromises the reaction efficiency, and, as
expected, degassing with nitrogen was shown to improve the
yield (entry 1 vs 9).20 Finally, the reaction time could be
including the electron-withdrawing cyano group (5), methyl
ester (7), primary amide (10), and free carboxylic acid (11).
For substrates that were insoluble in DCM, more polar
solvents were employed without diminishing yields (entries
10−12 and 22). More electron-rich substituents such as 4-
carbinol (4), 4-benzyloxy (6), 3-hydroxy (12), and 3,5-
dimethyl (15) pyridines were also compatible. Furthermore,
this method does not result in the cleavage of benzyl ethers of
the pyridine under the photoreductive conditions.21 Hetero-
aromatics containing halogens at any position were tolerated
without any observable hydrodehalogenation (entries 8, 9, 13,
14, and 20). Oxides of quinolines and isoquinolines also
performed well under the reaction conditions, affording their
corresponding reduced products in modest yields (entries 17−
20). Finally, several other heteroarene N-oxides were
successfully deoxygenated in good yield, including azaindole,
bipyridine, benzopyrazine, and benzo[c]cinnoline (entries 21−
24). Attempts at using 4-alkyl-substituted Hantzsch esters to
affect the sequential radical alkylation and deoxygenation did
not result in much success, and only trace product was
observed.22
shortened by the use of a higher energy light source (λmax
=
410 nm) to ensure the complete overlap of the LED emission
with Hantzsch ester’s absorbance (entry 10).
Having optimized the reaction conditions, we then examined
a variety of functionalized pyridine N-oxides and other
heteroaryl N-oxides to evaluate the scope of the transformation
(Scheme 2). A variety of electronically diverse mono- and
polysubstituted pyridine N-oxides were well tolerated without
any observed reduction of the pendant functionalities,
B
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Next, we explored the feasibility of our system for the
photoreduction of nitroaromatic compounds. Interestingly,
upon the irradiation of a 1:3 mixture of 4-nitrotoluene and
Hantzsch ester in DCM, only the corresponding hydroxyl-
amine was obtained. No further reduction was observed upon
either the addition of an excess of Hantzsch ester or heating to
45 °C. As with the previously described N-oxide deoxygena-
tion, the reduction of nitroarenes also featured good functional
group compatibility, selectively producing a variety of
substituted hydroxylamines (Scheme 3). Substrates bearing
electron-donating groups required extended reactions times,
whereas those with electron-withdrawing groups underwent
deoxygenation more rapidly.
c
Scheme 3. Photoreduction of Nitroarenes
Figure 1. UV−vis spectra of (a) 4-phenylpyridine N-oxide 2 (red line,
0.050 M in DCM), Hantzsch ester 1 (black line, 0.050 M in DCM),
and an equimolar mixture of 2 and 1 (0.050 M in DCM) and (b)
methyl 4-nitrobenzoate (red line, 0.050 M in DCM), 1 (black line,
0.050 M in DCM), and an equimolar mixture of methyl 4-
nitrobenzoate and 1 (0.050 M in DCM). (c) Shift of the methyl
resonance of 1 in the presence of equimolar 2 (0.10 M in CDCl3). (d)
Job plot of 1 and 2 (0.050 M in CH2Cl2) at 435 nm.
Scheme 4. Proposed EDA Complexes between 1 and 2
a
b
Run for 44 h. 1H NMR yields using 1,3,5-trimethoxybenzene as an
c
external standard. Reactions run on a 0.30 mmol scale.
To understand the reaction mechanism, we conducted
several spectroscopic experiments to determine whether
Hantzsch ester 1 was undergoing photoexcitation without
preorganization or whether an EDA complex was formed
between 1 and either substrate, which could help facilitate
electron transfer between them. We first analyzed 1 using UV−
vis spectroscopy and found that it alone does absorb within the
emission range of our light-emitting diodes (LEDs), suggesting
that it can undergo direct photoexcitation to generate the
highly reducing excited-state species (Figure 1a).12 However,
in the presence of either 4-phenylpyridine N-oxide 2 or methyl
4-nitrobenzoate, a bathochromic shift was observed, support-
ing the formation of an EDA complex between the reactants
(Figure 1a,b).16h,i 1H NMR experiments were also performed
and further corroborate this hypothesis. The mixing of neutral,
electron-rich, or electron-deficient pyridine N-oxides with
excited state of the dihydropyridine and afforded the
deoxygenated product.25
In conclusion, we have developed a reductive deoxygenation
of heteroaryl N-oxides and the reduction of nitroarenes to the
corresponding hydroxylamines via visible-light photoexcitation
of Hantzsch ester. These reactions are operationally simple,
can be performed under ambient conditions without the
exclusion of moisture or air, proceed smoothly in the presence
of a variety of functional groups, and do not require the use of
an expensive photocatalyst. Finally, spectroscopic studies
support the formation of an EDA complex between Hantzsch
ester and pyridine N-oxides or nitroarenes.
1
Hantzsch ester results in a shift of all H NMR resonances
compared with each substrate alone (Figure 1c; see the SI for
details). A Job plot was also constructed, which indicated that a
1:1 ratio of donor and acceptor was involved in the EDA
complex of 1 and 2 (Figure 1d).23 Whereas these data suggest
the formation of an EDA complex between the reactants, the
mode of interaction is not readily discernible. One possibility is
π-stacking between 1 and pyridine N-oxide (Scheme 4, top),
which has been previously proposed to occur between 1 and
N-alkylpyridinium salts.16i The alternative pathway may
involve Hantzsch ester as a hydrogen-atom donor with the
N-oxide as an acceptor (Scheme 4, bottom).24 Finally, in
further support of our findings, a similar photoreduction of
pyridine N-oxide by 1-benzyl-1,4-dihydronicotinamide under
UV irradiation was previously reported, wherein the authors
demonstrate that the N-oxide was quenching the singlet
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04632.
General experimental details, procedures, and character-
ization data for all products (PDF)
C
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Photocatalysis: Does it Make a Difference in Organic Synthesis?
Angew. Chem., Int. Ed. 2018, 57, 10034−10072 and references therein.
(9) For selected examples, see: (a) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-
Selective Reductive Coupling of Alkenylpyridines with Aldehydes and
Imines via Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem.
Soc. 2017, 139, 5003−5006. (b) Lackner, G. L.; Quasdorf, K. W.;
Overman, L. E. Direct Construction of Quaternary Carbons from
Tertiary Alcohols via Photoredox-Catalyzed Fragmentation of tert-
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15345. (c) Park, G.; Yi, S. Y.; Jung, J.; Cho, E. J.; You, Y. Mechanism
and Applications of the Photoredox Catalytic Coupling of Benzyl
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McTeague, T. A.; Johannes, J. W. Nickel-Catalyzed Photoredox-
Mediated Cross-Coupling of Aryl Electrophiles and Aryl Azides. ACS
Catal. 2018, 8, 9120−9124.
AUTHOR INFORMATION
■
Corresponding Authors
Mikhail O. Konev − Department of Chemistry, University of
Hamburg, Hamburg 20146, Germany;
Email: mikhail.konev@uni-hamburg.de
Axel Jacobi von Wangelin − Department of Chemistry,
University of Hamburg, Hamburg 20146, Germany;
orcid.org/0000-0001-7462-0745; Email: axel.jacobi@uni-
hamburg.de
Other Author
Luana Cardinale − Department of Chemistry, University of
Hamburg, Hamburg 20146, Germany
(10) Nakajima, K.; Nojima, S.; Sakata, K.; Nishibayashi, Y. Visible-
Light-Mediated Aromatic Substitution Reactions of Cyanoarenes with
4-Alkyl-1,4-dihydropyridines through Double Carbon−Carbon Bond
Cleavage. ChemCatChem 2016, 8, 1028−1032.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04632
́
́
(11) (a) Gutierrez-Bonet, A.; Tellis, J. C.; Matsui, J. K.; Vara, B. A.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This Letter is dedicated to Professor Jim Vyvyan (Western
Washington University) on the occasion of his 50th birthday.
We thank the University of Hamburg for technical support.
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