Synthesis of 2,3-Dihydro-4-pyridones, 4-Quinolones, and 2,3-Dihydro-4-azocinones by Visible-Light Photocatalytic Aerobic Dehydrogenation

Article abstract of DOI:10.1002/ejoc.201900584

The synthesis of 2,3-dihydro-4-pyridones and 4-quinolones was realized by visible-light mediated photoredox-catalyzed aerobic dehydrogenation of 4-piperidones and 2,3-dihydro-4-quinolones. This method enables the synthesis of cyclic enaminones in up to 89

Full text of DOI:10.1002/ejoc.201900584

A Journal of
Accepted Article
Title: Synthesis of 2,3-Dihydro-4-Pyridones, 4-Quinolones and 2,3-
Dihydro-4-Azocinones by Visible-Light Photocatalytic Aerobic
Dehydrogenation
Authors: Adrian Sevenich, Paulina Sophie Mark, Torsten Behrendt,
and Till Opatz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900584
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
Synthesis of 2,3-Dihydro-4-Pyridones, 4-Quinolones and 2,3-
Dihydro-4-Azocinones by Visible-Light Photocatalytic Aerobic
Dehydrogenation
Adrian Sevenich,[a] Paulina Sophie Mark,[a] Torsten Behrendt,[a] Jonathan Groß,[a] and Till Opatz*[a]
Abstract: The synthesis of 2,3-dihydro-4-pyridones and 4-quinolones
was realized by visible-light mediated photoredox-catalyzed aerobic
dehydrogenation of 4-piperidones and 2,3-dihydro-4-quinolones. This
method enables the synthesis of cyclic enaminones in up to 89% yield
under mild and eco-friendly conditions and with a high tolerance of
functional groups using oxygen as an inexpensive terminal oxidant
and rhodamine 6G as a readily available organic photocatalyst. The
process can be extended to access 2,3-dihydro-4-azocinones in up to
62% yield via a [2+2] cycloaddition/ring-expansion sequence in a
telescoping one-pot reaction. Hence, a protocol for the synthesis of
three different types of N-heterocycles was developed on the same
general transformation.
suffer from lengthy sequences, the use of expensive or
ecologically problematic reagents or catalysts and, most notably,
stoichiometric amounts of oxidants being required to effect the
dehydrogenation. First achievements to replace stoichiometric
reagents by oxygen as terminal oxidant have been reported by
Introduction
Due to the vinylogous transposition of the reactivity of the amine
nitrogen and the carbonyl group, enaminones show a versatile
reactivity pattern.[1] Their simple cyclic representatives such as
2,3-dihydro-4-pyridines are attractive building blocks and can e.g.
be used as precursors for piperidine-based target molecules.[2]
Consequently, they have been applied as building blocks for
drugs[3] or for alkaloid natural products such as indolizidines and
quinolizidines.[1a, 2a, 2c, 4] In addition, they represent key structures
in drug candidates like peptidomimetic opioids,[5] flavivirus
inhibitors[6] and antibacterial oxazolidinones.[7] Their benzo-fused
relatives, the 4-quinolones, are one of the largest class of
antimicrobial agents[8] and have recently attracted further
attention due to their antitumor and anti-HIV activity.[8b, 8c, 9]
Dehydrogenation has been used as a direct strategy to
access cyclic enaminones, since preformed heterocycles can
serve as the starting materials.[2c, 3c, 10] To this end, multistep
procedures based on the Polonovski reaction[10a, 10d, 10g] or the
Saegusa oxidation[7a, 10m] have been used extensively. Among the
one-step procedures, Hg(OAc)2[10b, 10f, 10k] and DDQ[10e, 10i, 10n] have
been applied by various groups. Nicolaou et al. found complexes
of IBX and various amine-N-oxides to enable the reaction under
10j, 10r]
mild condition.[10h,
However, these procedures generally
Scheme 1. Overview of catalytic one-step syntheses of cyclic enaminones
by aerobic dehydrogenation.
[a]
A. Sevenich, P. S. Mark, T. Behrendt, J. Groß, Prof. Dr. Till Opatz
Institute of Organic Chemistry, Johannes Gutenberg University,
Duesbergweg 10-14, 55128 Mainz, Germany
E-Mail: opatz@uni-mainz.de
Stahl et al. who proposed a Pd(DMSO)2(TFA)2 catalyst which
enables the dehydrogenation of cyclic ketones (Scheme 1).[10l]
The group of Mizuno found a heterogeneous catalyst system
consisting of gold nanoparticles supported on manganese oxide
https://ak-opatz.chemie.uni-mainz.de/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
to perform the aerobic dehydrogenation of β-heteroatom-
being slightly superior (entry 5). Further evaluation of different
solvents (entries 6 to 11) revealed DMF to be the best choice.
substituted ketones.[10p] Recently,
a photoredox catalyzed
Table 1. Optimization studies for the photocatalytic dehydrogenation.(a)
approach was reported by Jiang et al. using the non-commercial
dicyanopyrazine chromophore (DPZ) as a photocatalyst in
combination with oxygen to obtain 2,3-dihydro-4-pyridones and 4-
quinolones on a limited scale.[10o]
Photoredox catalysis through organic dyes has proven to be
a valuable and often eco-friendly tool for performing a large
variety of selective transformations on amines under mild
conditions,[11] which were also investigated in our labs.[12] It was
therefore attempted to overcome the drawbacks of above-
mentioned protocols for the synthesis of cyclic enaminones using
an inexpensive commercially available organic dye as catalyst
and oxygen as sustainable oxidant.
Partially saturated azocines have recently attracted attention
due to their occurrence in natural products such as the
manzamine alkaloids[13] and their various biological activities,[13a,
14]
for example against leishmaniasis.[13a] To access this
interesting group of eight-membered N-heterocycles, ring-
expansion has become a common strategy which can e.g. be
initiated by [2+2] cycloaddition of acetylene esters and cyclic
enamine containing structures.[14a, 15] In this context, it appeared
possible to combine the photocatalytic dehydrogenation step with
a subsequent light-independent reaction like a [2+2] cycloaddition
ultimately leading to ring-expansion. This would provide a direct
access to eight-membered N-heterocycles from a completely
saturated six-membered nitrogen containing precursor via the
intermediate enaminone.
Here, we describe the synthesis of cyclic enaminones like 2,3-
dihydro-4-pyridones and 4-quinolones by visible light mediated
aerobic dehydrogenation and exploited their reactivity to provide
access to another class of N-heterocycles, namely 2,3-dihydro-4-
azocinones in a one-pot reaction.
Entry
1
Cat. (mol%)
3 (5)
Solvent
DMF
DMF
DMF
DMF
DMF
DMSO
MeOH
DCM
PhMe
ACN
THF
1a (%)(b)
<1
<1
<1
13
15
58
96
42
85
37
15
65
29
10
<1
<1
4
2a (%)(b)
58(c)
36
2
5 (5)
3
4 (5)
49
4
6 (5)
53
5
7 (5)
61
6
7 (5)
21
7
7 (5)
2
8
7 (5)
35
9
7 (5)
9
10
11
12
13
14
15
16
17
18
19
20
21
7 (5)
42
7 (5)
49
Results and Discussion
7 (5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
24(d)
47
We started our optimization studies in terms of reaction yield
7 (10)
7 (2)
by evaluating various xanthene dyes which have commonly been
11h, 12a]
used for amine oxidations.[11b,
Interestingly, the most
66
frequently used catalysts rose bengal (RB, 5) and eosin Y (EY, 4)
gave no clean reactions (Table 1, entries 2 and 3). Although the
starting material was consumed very rapidly, the product yield
remained always moderate, at both low and high conversion,
indicating that 2 might not be stable under these conditions.
Indeed, the C=C bond cleavage of enamines and enaminones
under visible light catalyzed aerobic conditions using RB and EY
is well documented.[16] Even though there have been debates as
to whether or not singlet oxygen is involved in this reaction,[16c] it
is obvious that these conditions are not suitable and overcoming
this issue would be a key challenge for the outlined approach. The
low yields of 2 observed using RB and EY are in agreement with
the observations by Jiang and may have prompted them to use a
non-commercial dye.[10o] Gratifyingly, fluorescein (3) and
rhodamine 6G (7) gave the product 2 in satisfactory yields, with 7
7 (1.5)
7 (1)
72
77 (70)(e)
68
7 (0.5)
7 (0.1)
-
7
59
96
98
96
0
7 (1)
0(f)
7 (1)
0(g)
(a)Reaction conditions: 1a (0.3 mmol), 1 mL dry solvent, RGB LED stripe
(~80 W) on green. (b)Yield determined by 1H-NMR using 1,4-
bis(trimethylsilyl)benzene as internal standard. (c)RGB LED stripe (~80 W)
on blue. (d)Air was used instead of oxygen. (e)Isolated yield in brackets. (f)In
the dark. (g)Argon instead of oxygen atmosphere.
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
Replacement of oxygen by air led to reduced conversion
showing that a fast catalyst quenching is vital for fast reaction
kinetics. Variation of the catalyst loading (entries 13 to 18) showed
a faster reaction at lower catalyst loading, with 1 mol% as the
optimum (entry 16). Most probably, at higher catalyst loading, light
absorption is limited to a very small volume close to the surface
of the vial and collision of excited catalyst with substrate
molecules during the lifetime of the excited state is less likely.
Further decreasing the catalyst loading resulted in a slightly
decreased yield and conversion but a still satisfactory yield of 59%
was achieved with only 0.1 mol% catalyst (entry 18), which is in
good agreement with previous observations of organic dyes in
part being highly efficient at even low catalyst loadings.[12a] In the
absence of catalyst, light or oxygen the starting material remained
untouched (entry 19 to 21). Various additives, light sources or
variations of oxygen delivery were also taken into account in our
studies but did not produce better results in terms of product yield
or reaction time (see SI for further screenings).
With the improved reaction conditions, the scope of this
reaction was evaluated (Scheme 2). A variety of functional groups
were tolerated and moderate to high yields (2b, 2d-e, 2j-l, 2s)
could be achieved with electron donating and withdrawing groups
such as Me, OMe, F, Cl, or CONHMe. Strongly electron
withdrawing groups like CF3 and NO2 led to increased reaction
times and lower yields (2h, 2i). Even Br- and I-substituents were
tolerated, although partial halogen transfer under formation of
dihalogenated species was observed (2f, 2g). In the case of the
3-carboxy substituted starting material, product 2t was formed as
the sole regioisomer. The moderate yield can be partly explained
by the formation of 2t’ as a by-product, most probably caused by
a Bayer-Villiger reaction of 2t with H2O2 generated in the course
of the reaction. At prolonged reaction times, over-oxidation to 4-
pyridons and oxidative cleavage of the enaminone’s C=C bond
(vide supra) were frequently observed as side reactions of various
substrates. The yields of 4-quinolones (2o, 2p) were generally
higher and in the range of 90%, which can be explained by
increased product stability and fewer possibilities of side reactions
such as over-oxidation. In addition, they provide better
stabilization of the intermediates 9 and 10 (Scheme 3) which
seem to be crucial for a rapid and clean reaction. On the other
hand, N-alkyl substituents devoid of any stabilizing effect (2u)
gave only unsatisfactory conversions, presumably due to the
lower HOMO energy of the unconjugated nitrogen lone pair. The
same was observed with ortho-substituents (2w, 2x) which force
the aromatic ring out of conjugation with the lone pair, leading to
decreased orbital overlap according to DFT calculations (data not
shown). N-1-naphthyl substituents are however tolerated in the
reaction (2p, 2q).
Scheme 2. Scope of cyclic enaminones by photocatalytic dehydrogenation.
(a)Reaction conditions: 1 (0.3 mmol), 1 mL dry solvent, 7 (1 mol%), 1 atm O2,
RGB LED stripe (~80 W) on green, 25 °C. (b)Yield of recovered starting
material. (c)No extraction performed due to high polarity of product. (d)As
judged by 1H-NMR.
10 is formed, the latter undergoes rapid deprotonation to the more
stable enaminone 2 furnishing hydrogen peroxide as a by-product.
To demonstrate the synthetic value of this protocol, the
reaction was performed on a gram scale (Scheme 4). For this
purpose, a steady stream of oxygen was slowly bubbled through
the solution to ensure sufficient availability of the oxidant. Besides
an increase in reaction time, the dehydrogenation of 1a
proceeded smoothly to give the enaminone 2a in 60% isolated
yield.
A plausible reaction mechanism is depicted in Scheme 3.
After absorption of light, the catalyst 7 can react with substrate 1
to furnish the amine radical cation 9 by single-electron-transfer
(SET). Upon reaction with molecular oxygen through a second
SET step, the catalyst 7 is recycled leading to formation of a
superoxide radical anion capable of abstracting a hydrogen from
9.[17] By these means, the hydroperoxide anion and iminium ion
With ample amounts of the cyclic enaminone 2 in hand, the
[2+2] cycloaddition/ring-expansion sequence was to be optimized
and
the
applicability
of
the
photoredox-catalyzed
dehydrogenation to the synthesis of azocinone derivatives had to
be demonstrated (Table 2). The studies were begun using a
modified protocol of the microwave assisted cycloaddition of
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
DMAD (11a) reported by the Stanovnik laboratory.[15b] With the
aim to develop a one-pot reaction, rhodamine 6G (7) and DMF
Gradually decreasing the temperature led to longer reaction times
but significantly increased yields. Finally, the best results were
obtained when the reaction mixture was simply heated in an oil-
bath overnight (entry 7). In the end, a telescoped one-pot reaction
starting from 1a was performed proving the possibility to access
eight-membered N-heterocycles 12 directly from piperidones 1
(entry 8).
The scope of the one-pot synthesis of azocinones 12 from
piperidones 1 and acetylene dicarboxylates 11 is displayed in
Scheme 5. The reaction gave a variety of 2,3-dihydro-4-
azocinones in synthetically useful yields (12a-e). It appeared
tempting to investigate simple acetylenic esters 11c and 11d in
the one-pot reaction of 1a, but no conversion took place even at
120 °C and the enaminone 2a was the only product isolated in
both cases. Apparently, only very electron deficient acetylenes do
react with 2. Furthermore, we wondered whether
benzo[b]azocinone 12f could be obtained by reacting 1o with 11a
in this sequence but again, only the 4-quinolone 2o could be
isolated. This observation might be explained by the high stability
and hence low reactivity of the 4-quinolone 2o so that no
Scheme 3. Plausible reaction mechanism.
Scheme 4. Gram-scale synthesis of 2a.
were added to all screening reactions to imitate the conditions
after the dehydrogenation step. Indeed, the cycloaddition went
smoothly to yield directly the eight-membered heterocycle 12a.
A short screening of co-solvents (entries 1 to 4) revealed
acetonitrile to be the best choice of this group. Next, the reaction
temperature was investigated. At higher temperature, the reaction
was faster but a decrease in yield was observed (entry 5).
Table 2. Optimization studies for the photocatalytic dehydrogenation.(a)
Co-
cycloaddition takes place. A plausible mechanism of the
Entry
solvent
DMF
DCM
PhMe
ACN
ACN
ACN
ACN
ACN
Temp. (°C)
120
Time (h)
2a (%)(b)
12a (%)(b)
1
2
3
4
5
6
7
8
2
3
67
Scheme 5. Scope of the one-pot synthesis of azocine-derivatives from
piperidones. Reaction conditions: 1 (0.3 mmol), 1 mL dry DMF, 7 (1 mol%),
1 atm O2, RGB LED stripe (~80 W) on green, 25 °C, then: 1 mL co-solvent,
11 (3.0 eq.), 90 °C, oil-bath.
120
2
26
25
4
49
120
2
53
120
2
74
cycloaddition/ring-expansion sequence is illustrated in Scheme 6.
[2+2] cycloaddition of acetylene ester 11 and enaminone 2 furnish
cyclobutene intermediate 13. The cycloaddition can be either
concerted (path a) or stepwise (path b).[15b] There had been some
debate about the ring opening mechanism of cis-bicyclo[4.2.0]oct-
7-ene-intermediates such as 13.[18] The isolation of cis,cis-
products in almost all cases has led to the assumption that ring
opening may occur in a disrotatory fashion, which would violate
150
1.5
6
3
68
105
12
7
79
90
17
88 (85) (c)
90
20
n.d.
(62) (c,d)
(a)Reaction conditions: 2a (0.3 mmol), 7 (1 mol%), 1 mL DMF, 1 mL co-
solvent, 11a (3.0 eq.), sealed vessel, microwave irradiation. (b)Yield
determined by 1H-NMR using 1,4-bis(trimethylsilyl)benzene as internal
standard, n.d. = not determined. (c)Isolated yields in brackets. Oil-bath
instead of microwave. (d)One-pot reaction starting from 1a.
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
the Woodward-Hoffmann rules. However, some studies have
functional groups and was successfully performed on a gram
scale. In addition, it can be extended to access azocinones in a
simple one-pot procedure. This versatile protocol could find
application in the synthesis of natural products and drug
precursors. Overcoming the necessity of N-aryl groups would
make this method even more versatile and could eventually
provide a general method to convert Mannich products into
enaminones. Furthermore, better control of oxygen supply to
increase efficiency and to avoid over-oxidation, potentially by
means of flow chemistry, will remain as challenge for further
investigations.
shown that trans,cis-products can be obtained under carefully
18d]
controlled and mild reaction conditions.[18c,
Recent studies
based on computational calculation revealed the conrotatory ring
opening, followed by isomerization to be the most likely
pathway.[18f] To determine the geometry of double bonds in 12a,
3JC-H coupling constants between the methine protons and
corresponding carbons were measured by CLIP-HSQMBC[19] and
compared to literature values. Usually a cis-arrangement between
C and H results in smaller values than in the case of a trans-
arrangement (see Figure S2 in the SI).[20] From the measured
Experimental Section
General information: All chemicals were obtained from commercial
suppliers and used without purification unless stated otherwise. Anhydrous
DCM was distilled from calcium hydride under nitrogen. Anhydrous toluene
and THF were distilled from sodium/benzophenone under nitrogen. Extra
dry DMF, ACN, MeOH and DMSO were purchased from Acros Organics
(AcroSeal®). The eluents for column chromatography cHex and EtOAc
were purchased in technical grade and distilled prior to use. Chloroform-d
was stored over sodium sulfate and alumina (Brockmann activity I).
Chromatographic purification was performed on silica gel (35–70 µm,
Acros Organics). Automated flash chromatography was performed on an
IsoleraTM Flash Purification System (Biotage) with an integrated diode
array detector using SNAP KP-Sil cartridges. TLC was carried out on silica
plates (TLC Silica 60 F254 by Merck). NMR spectra were recorded on a
Bruker Avance-III HD (1H-NMR: 300 MHz, 13C-NMR: 75.5 MHz), a Bruker
Avance-II (1H-NMR: 400 MHz, 13C-NMR: 100.6 MHz) or a Bruker Avance-
III (1H-NMR: 600 MHz, 13C-NMR: 151.1 MHz) spectrometer. Chemical
shifts are referenced to residual solvent signals (CDCl3: 7.26 ppm and
77.16 ppm, DMSO-d6: 2.50 ppm and 39.52 ppm for 1H-NMR and 13C-NMR
respectively) and reported relative to TMS. IR spectra were recorded on a
FTIR-spectrometer (Bruker Tensor 27) with a diamond ATR unit and are
Scheme 6. Plausible mechanism of the cycloaddition/ring-expansion
values, the (2E,4E)-geometry was rationalized for 12a which is
consistent with the geometry of similar compounds.[15b,
18e]
reported in terms of frequency of absorption 휈̅
[cm–1]. ESI mass spectra
Although none of the intermediates 14 have been observed, we
assume the mechanism to proceed by a conrotatory electrocyclic
ring opening of 13. The isomerisation to 12 in the cause of the
reaction should be promoted by the push-pull character of
intermediate 14. The same geometry of 12 was obtained, when
the reaction was performed either in a one-pot fashion starting
from 1a or from isolated 2a, which shows that product geometry
was not affected by any by-product from the previous
dehydrogenation step, such as H2O2.
were recorded on a 1200-series HPLC-system or a 1260-series Infinity II
HPLC-system (Agilent-Technologies) with binary pump and integrated
diode array detector coupled to a LC/MSD-Trap-XTC-mass spectrometer
(Agilent-Technologies) or
a LC/MSD Infinitylab LC/MSD (G6125B
LC/MSD). HRMS spectra were recorded on a Micromass-Q-TOF-Ultima-
3-mass spectrometer (Waters) with LockSpray-interface and a suitable
external calibrant. Melting points were determined in open capillary tubes
using a Krüss-Optronic KSP 1 N thermoelectric melting point meter.
Reactions accelerated by microwave heating were performed in a
Discover monomode apparatus from CEM in glass vials sealed with septa
under constant temperature.
Conclusions
Compounds 1a-f, 1h-i, 1k-n, 1q-s,[21] 1i,[22] 1o,[23] 1p,[23] and 1t[24] were
prepared by known procedures and their spectroscopic data are in
accordance to those reported in the literature. Compounds 1u and 1v were
obtained from commercial suppliers. Compound 1g, 1j, 1w and 1x[21] were
prepared by known procedures but have not been characterized yet.
In summary, a mild and environmentally benign protocol for
the synthesis of 2,3-dihydro-4-pyridones and 4-quinolones by
means of visible-light mediated dehydrogenation using oxygen as
a
terminal oxidant and inexpensive rhodamine 6G as
photocatalyst was developed. To the best of our knowledge, there
is currently no cheaper and more sustainable way to effect this
transformation. The reported methods tolerates a variety of
1-(4-iodophenyl)piperidin-4-one (1g): Yield: 64.9%, yellow solid; Rf =
0.39 (cHex/EtOAc = 3:1); mp: 98.1–100.2 °C; 1H-NMR, COSY (400 MHz,
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
Chloroform-d) δ 7.57–7.52 (m, 2H, H3’, H5’), 6.75–6.71 (m, 2H, H2’, H6’),
3.58 (t, J = 6.1 Hz, 4H, H2, H6), 2.53 (t, J = 6.1 Hz, 4H, H3, H5); 13C-NMR,
HSQC, HMBC (101 MHz, Chloroform-d) δ 207.75 (C4), 148.80 (C1’),
138.24 (C3’, C5’), 117.89 (C2’, C6’), 81.47 (C4’), 48.40 (C2, C6), 40.59
(C3, C5); IR: 2824, 1716, 1583, 1490, 1381, 1357, 1315, 1221, 1086, 989,
808; ESI-MS: 302.1 (100%) [M+H]+; HRMS (ESI): m/z = 302.0034 ([M+H]
+, calc. 302.0036).
1-phenyl-2,3-dihydropyridin-4(1H)-one (2a): Yield: 36.4 mg, 0.210
mmol, 70%, orange solid; Rf = 0.24 (cHex/EtOAc = 2:3); mp: 89–90 °C; 1H-
NMR, COSY (400 MHz, Chloroform-d) δ 7.44 (d, J = 7.8 Hz, 1H, H6), 7.43–
7.33 (m, 2H, H3’, H5’), 7.20–7.10 (m, 1H, H4’), 7.12–7.07 (m, 2H, H2’, H6’),
5.22 (d, J = 7.8 Hz, 1H, H5), 4.00 (t, J = 8.1 Hz, 2H, H2), 2.65 (t, J = 8.1
Hz, 2H, H3); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 192.04
(C4), 149.71 (C6), 145.23 (C1’), 129.74 (C3’, C5’), 124.47 (C4’), 118.29
(C2’, C6’), 102.17 (C5), 47.66 (C2), 36.05 (C3); IR: 3058, 1645, 1572, 1494,
1315, 1219, 1178, 758, 694, 530; ESI-MS: 174.0 (100) [M+H]+, 196.0 (20)
[M+Na]+. The analytical data are consistent with those reported in the
literature.[2c]
N-methyl-4-(4-oxopiperidin-1-yl)benzamide (1j): Yield: 61.4%, yellow
solid; Rf = 0.25 (100% EtOAc); mp: 134.6–137.6 °C; 1H-NMR, COSY (400
MHz, Chloroform-d) δ 7.74–7.69 (m, 2H, H3’, H5’), 6.93–6.88 (m, 2H, H2’,
H6’), 6.30–6.17 (m, 1H, NH), 3.69 (t, J = 6.1 Hz, 4H, H2, H6), 2.97 (d, J =
4.8 Hz, 3H, CH3), 2.54 (t, J = 6.1 Hz, 4H, H3, H5); 13C-NMR, HSQC, HMBC
(101 MHz, Chloroform-d) 207.65 (C4), 167.80 (CONH), 151.03 (C1’),
128.73 (C3’, C5’), 124.67 (C4’), 113.94 (C2’, C6’), 47.28 (C2, C6), 40.46
(C3, C5), 26.86 (CH3); IR: 3336, 2968, 2901, 1712, 1606, 1551, 1509,
1387, 1358, 1297, 1219, 768; ESI-MS: 233.2 (100%) [M+H]+, 255.2
(38.5%) [M+Na]+, 487.4 (20.9%) [2M+Na]+; HRMS (ESI): m/z = 233.1282
([M+H] +, calc. 233.1285).
1-(p-tolyl)-2,3-dihydropyridin-4(1H)-one (2b): Yield: 42.0 mg, 0.224
mmol, 75%, orange solid; Rf = 0.23 (cHex/EtOAc = 2:3); mp: 69.5–71.4 °C;
1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.39 (d, J = 7.7 Hz, 1H, H2),
7.20–7.15 (m, 2H, H3’, H5’), 7.01–6.96 (m, 2H, H2’, H6’), 5.19 (d, J = 7.7
Hz, 1H, H3), 4.00–3.93 (m, 2H, H6), 2.66–2.60 (m, 2H, H5), 2.33 (s, 3H,
CH3); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 191.96 (C4),
150.01 (C2), 142.95 (C1’), 134.36 (C4’), 130.23 (C3’, C5’), 118.46 (C2’,
C6’), 101.58 (C3), 47.88 (C6), 36.02 (C5), 20.81 (CH3); IR: 1644, 1573,
1513, 1304, 1272, 1215, 1176, 1105, 1027, 800; ESI-MS: 188.1 (100%)
[M+H]+. The analytical data are consistent with those reported in the
literature.[10o]
1-(o-tolyl)piperidin-4-one (1w): Yield: 70.4%, yellow solid; Rf = 0.21
(cHex/EtOAc = 20:1); mp: 66.9–68.7 °C; 1H-NMR, COSY (400 MHz,
Chloroform-d) δ 7.25–7.21 (m, 1H, H3’), 7.21–7.16 (m, 1H, H5’), 7.06–7.01
(m, 2H, H4’, H6’), 3.22 (t, J = 6.1 Hz, 4H, H2, H6), 2.61 (t, J = 6.1 Hz, 4H,
H3, H5), 2.40 (s, 3H, CH3); 13C-NMR, HSQC, HMBC (101 MHz,
Chloroform-d) δ 208.75 (C4), 150.81 (C1’), 132.72 (C2’), 131.25 (C3’),
126.74 (C5’), 123.89 (C4’), 119.48 (C6’), 52.11 (C2, C6), 42.28 (C3, C5),
17.94 (CH3); ESI-MS: 190.2 (100%) [M+H]+; HRMS (ESI): m/z = 190.1225
([M+H] +, calc. 190.1226).
1-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (2c): Yield: 22.0
mg, 0.108 mmol, 36.1%, yellow solid; Rf = 0.13 (cHex/EtOAc = 2:3); mp:
102.2–102.9 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) 7.34 (d, J = 7.7
Hz, 1H, H2), 7.06–7.02 (m, 2H, H2‘, H6‘), 6.93–6.88 (m, 2H, H3‘, H5‘), 5.17
(d, J = 7.7 Hz, 1H, H3), 3.95 (dd, J = 8.1, 7.2 Hz, 2H, H6), 3.81 (s, 3H,
CH3), 2.64 (dd, J = 8.1, 7.2 Hz, 2H, H5); 13C-NMR, HSQC, HMBC (101
MHz, Chloroform-d) δ 191.85 (C4), 156.97 (C4‘), 150.57 (C2), 139.03 (C1‘),
120.51 (C3‘, C5‘), 114.90 (C2‘, C6‘), 101.16 (C3), 55.73 (CH3), 48.48 (C6),
36.05 (C5); IR: 1629, 1575, 1510, 1463, 1306, 1287, 1242, 1221, 1173,
1038, 806; ESI-MS: 204.1 (100%) [M+H]+, 226.1 (30.7%) [M+Na]+, 429.2
(35.7%) [2M+Na]+. The analytical data are consistent with those reported
in the literature.[10o]
1-(2-chlorophenyl)piperidin-4-one (1x): Yield: 31.7%, colorless solid; Rf
= 0.50 (cHex/EtOAc = 3:1); mp: 83.1–83.5 °C; 1H-NMR, COSY (400 MHz,
Chloroform-d) δ 7.40 (dd, J = 7.9, 1.5 Hz, 1H, H3’), 7.23 (ddd, J = 8.0, 7.3,
1.5 Hz, 1H, H5’), 7.06 (dd, J = 8.0, 1.5 Hz, 1H, H6’), 7.04–6.99 (m, 1H,
H4’), 3.34 (t, J = 6.1 Hz, 4H, H2, H6), 2.64 (t, J = 6.1 Hz, 4H, H3, H5); 13C-
NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 208.52 (C4), 148.66 (C1’),
130.79 (C3’), 129.06 (C2’), 127.74 (C5’), 124.38 (C4’), 120.90 (C6’), 51.49
(C2, C6), 42.02 (C3, C5); IR: 2816, 1716, 1588, 1481, 1379, 1311, 1209,
1958, 1039, 756; ESI-MS: 210.1 (100%) [M+H]+, 212.1 (43.0%) [M+H]+;
HRMS (ESI): m/z = 210.0680 ([M+H] +, calc. 210.0680).
1-(4-fluorophenyl)-2,3-dihydropyridin-4(1H)-one (2d): Yield: 32.4 mg,
0.169 mmol, 57%, orange solid; Rf = 0.12 (cHex/EtOAc = 2:3); mp: 110.2–
113.4 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.35 (d, J = 7.8 Hz,
1H, H2), 7.09–7.04 (m, 4H, H2‘, H3‘, H5‘, H6‘), 5.20 (d, J = 7.8 Hz, 1H, H3),
3.96 (dd, J = 8.1, 7.2 Hz, 2H, H6), 2.64 (dd, J = 8.1, 7.2 Hz, 2H, H5); 13C-
NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 191.90 (C4), 159.72 (d,
J = 244.9 Hz, C4‘), 150.02 (C2), 141.69 (d, J = 2.9 Hz, C1‘), 120.31 (d, J
= 8.1 Hz, C2‘, C6‘), 116.49 (d, J = 22.8 Hz, C3‘, C5‘), 102.05 (C3), 48.20
(C6), 35.98 (C5); IR: 1632, 1577, 1508, 1316, 1306, 1276, 1214, 1181,
1164, 832, 818, 499; ESI-MS: 192.0 (100%) [M+H]+, 214.0 (12.1%)
[M+Na]+. The analytical data are consistent with those reported in the
literature.[10o]
General procedure for the photoredox-catalyzed aerobic
dehydrogenation: A 10 mL glass vial was charged with the 4-piperidone
or 2,3-dihydro-4-quinolone 1 (0.300 mmol, 1.00 eq.), rhodamine 6G (7)
(0.003 mmol, 1 mol%) and anhydrous DMF (1.00 mL). The vial was sealed
with a rubber septum and the mixture was stirred until rhodamine 6G was
completely dissolved. The reaction vessel was flushed with oxygen for 2
minutes and placed inside a flask, covered with LED stripes (see SI for
irradiation setup). The mixture was stirred under irradiation with green LED
stripes, until the starting material 1 was almost consumed completely (as
judged by TLC or LC-MS analysis). Water was added and the mixture was
extracted with Et2O to remove most of the DMF. For 2j and 2t the
extraction step was skipped due to the high polarity of these compounds.
The organic phases were combined and the solvent was removed in vacuo.
The crude product was purified by automated flash column
chromatography (SiO2, cHex/EtOAc).
1-(4-chlorophenyl)-2,3-dihydropyridin-4(1H)-one (2e): Yield: 39.4 mg,
63%, colorless solid; Rf = 0.27 (cHex/EtOAc = 1:4); mp: 98.7–99.8 °C; 1H-
NMR, COSY (400 MHz, Chloroform-d) δ 7.37 (d, J = 7.8 Hz, 1H, H2), 7.35–
7.30 (m, 2H, H3’, H5’), 7.04–6.99 (m, 2H, H2’, H6’), 5.22 (d, J = 7.8 Hz,
1H, H3), 3.99–3.92 (m, 2H, H6), 2.67–2.61 (m, 2H, H5); 13C-NMR, HSQC,
HMBC (101 MHz, Chloroform-d) δ 191.91 (C4), 149.18 (C2), 143.81 (C1’),
129.75 (C3’, C5’), 129.70 (C4’), 119.47 (C2’, C6’), 102.74 (C3), 47.71 (C6),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
35.97 (C5); IR: 3058, 2836, 1637, 1565, 1492, 1312, 1300, 1216, 1175,
1093, 798; ESI-MS: 208.0 (100%) [M+H]+, 209.9 (32.8%) [M+H]+; HRMS
(APCI): m/z = 208.0525 ([M+H]+, calc. 208.0524).
(m, 2H, H6), 2.97 (d, J = 4.8 Hz, 3H, CH3), 2.68–2.62 (m, 2H, H5); 13C-
NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 192.11 (C4), 167.15 (CO),
148.55 (C2), 147.22 (C1‘), 129.96 (C4‘), 128.73 (C3‘, C5‘), 117.26 (C2‘,
C6‘), 103.44 (C3), 47.26 (C6), 35.99 (C5), 26.95 (CH3); IR: 1636, 1563,
1504, 1409, 1304, 1277, 1218, 1178, 767, 728; ESI-MS: 231.2 (100%)
[M+H]+, 253.2 (47.5%) [M+Na]+, 483.1 (19.9%) [M+Na]+; HRMS (ESI): m/z
= 231.1130 ([M+H] +, calc. 231.1128).
1-(4-bromophenyl)-2,3-dihydropyridin-4(1H)-one (2f): Yield: 24.8 mg,
33%, yellow solid; Rf = 0.17 (cHex/EtOAc = 2:3); mp: 122.6–124.5 °C; 1H-
NMR, COSY (400 MHz, Chloroform-d) δ 7.50–7.46 (m, 2H, H3‘, H5‘), 7.38
(d, J = 7.8 Hz, 1H, H2), 7.00–6.94 (m, 2H, H2‘, H6‘), 5.24 (d, J = 7.8 Hz,
1H, H3), 3.97 (dd, J = 8.0, 7.1 Hz, 2H, H6), 2.66 (dd, J = 8.0, 7.1 Hz, 2H,
H5); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 191.93 (C4),
149.02 (C2), 144.30 (C1‘), 132.72 (C3‘, C5‘), 119.77 (C2‘, C6‘), 117.22
(C4‘), 102.93 (C3), 47.66 (C6), 36.02 (C5); IR: 1644, 1596, 1567, 1491,
1311, 1266, 1217, 1177, 821, 800; ESI-MS: 252.2 (99.5%), 254.0 (100%)
[M+H]+, 274.0 (9.2%), 276.0 (8.6%) [M+Na]+; HRMS (APCI): m/z =
252.0019 ([M+H] +, calc. 252.0019).
1-(m-tolyl)-2,3-dihydropyridin-4(1H)-one (2k): Yield: 34.3 mg, 0.183
mmol, 62%, yellow oil; Rf = 0.25 (cHex/EtOAc = 2:3); 1H-NMR, COSY (400
MHz, Chloroform-d) δ 7.43 (d, J = 7.8 Hz, 1H, H2), 7.25 (td, J = 7.6, 0.7
Hz, 1H, H5’), 6.94–6.98 (m, 1H, H6’), 6.92–6.87 (m, 2H, H2’, H4’), 5.20 (d,
J = 7.8 Hz, 1H, H3), 4.03–3.94 (m, 2H, H6), 2.68–2.59 (m, 2H, H5), 2.37
(s, 3H, CH3); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 192.11
(C4), 149.86 (C2), 145.23 (C1’), 139.79 (C3’), 129.53 (C5’), 125.31 (C6’),
119.07 (C4’), 115.42 (C2’), 101.89 (C3), 47.70 (C6), 36.03 (C5), 21.65
(CH3); IR: 1647, 1572, 1494, 1467, 1309, 1274, 1228, 1184, 778, 696; ESI-
MS: 188.1 (100%) [M+H]+, 210.0.1 (8.4%) [M+Na]+, 397.1 (8.6%)
[2M+Na]+; HRMS (APCI): m/z = 188.1071 ([M+H] +, calc. 188.1070).
1-(4-iodophenyl)-2,3-dihydropyridin-4(1H)-one (2g): Yield: 20.0 mg,
0.0669 mmol, 22%, orange solid; Rf = 0.19 (cHex/EtOAc = 2:3); mp: 158.5–
1
161.6 °C; H-NMR, COSY (400 MHz, Chloroform-d) δ 7.70–7.64 (m, 2H,
H3‘, H5‘), 7.38 (d, J = 7.8 Hz, 1H, H2), 6.88–6.83 (m, 2H, H2‘, H6‘), 5.25
(d, J = 7.8 Hz, 1H, H3), 3.97 (dd, J = 8.0, 7.1 Hz, 2H, H6), 2.66 (dd, J =
8.0, 7.1 Hz, 2H, H5); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ
191.94 (C4), 148.84 (C2), 144.97 (C1‘), 138.67 (C3‘, C5‘), 120.05 (C2‘,
C6‘), 103.10 (C3), 87.57 (C4‘), 47.55 (C6), 36.04 (C5); IR: 1649, 1594,
1572, 1488, 1312, 1299, 1264, 1247, 1218, 1177, 817; ESI-MS: 300.0
(100%) [M+H]+, 322.0 (9.9%) [M+Na]+; HRMS (APCI): m/z = 299.9878
([M+H] +, calc. 299.9880).
1-(3-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (2l): Yield: 39.8 mg,
0.196 mmol, 65%, orange solid; Rf = 0.18 (cHex/EtOAc = 2:3); mp: 67.3–
68.8 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.43 (d, J = 7.8 Hz,
1H, H2), 7.27 (t, J = 8.2 Hz, 1H, H5‘), 6.69–6.65 (m, 2H, H4‘, H6‘), 6.60 (t,
J = 2.3 Hz, 1H, H2‘), 5.21 (d, J = 7.8 Hz, 1H, H3), 3.97 (dd, J = 8.1, 7.1 Hz,
2H, H6), 3.81 (s, 3H, CH3), 2.64 (dd, J = 8.1, 7.1 Hz, 2H, H5); 13C-NMR,
HSQC, HMBC (101 MHz, Chloroform-d) δ 192.20 (C4), 160.71 (C3‘),
149.66 (C2), 146.43 (C1‘), 130.53 (C5), 110.56, 109.37 (C4‘, C6‘), 104.76
(C2‘), 102.15 (C3), 55.52 (CH3), 47.62 (C6), 35.99 (C5); IR: 1646, 1572,
1497, 1310, 1280, 1251, 1237, 1202, 1173, 1051; ESI-MS: 204.1 (100%)
[M+H]+, 226.1 (21.3%) [M+Na]+, 429.3 (20.1%) [2M+Na]+. The analytical
data are consistent with those reported in the literature.[10o]
1-(4-(trifluoromethyl)phenyl)-2,3-dihydropyridin-4(1H)-one (2h): Yield:
20.7 mg, 0.0858 mmol, 29%, yellow solid; Rf = 0.19 (cHex/EtOAc = 2:3);
mp: 119.2–121.8 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.66–
7.62 (m, 2H, H3’, H5’), 7.47 (d, J = 7.8 Hz, 1H, H2), 7.19–7.16 (m, 2H, H2’,
H6’), 5.32 (d, J = 7.8 Hz, 1H, H3), 4.07–4.01 (m, 2H, H6), 2.74–2.67 (m,
2H, H5); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 192.04 (C4),
148.27 (C2), 147.72 (C1’), 127.10 (q, J = 3.7 Hz, C3’, C5’), 125.97 (q, J =
33.1 Hz, C4’)*, 124.07 (q, J = 271.5 Hz, CF3)*, 117.54 (C2’, C6’), 104.08
(C3), 47.35 (C6), 36.08 (C5); *Outer quartet signals can hardly be seen
due to their low intensity; IR: 1642, 1563, 1519, 1313, 1283, 1219, 1196,
1173, 1103, 1068; ESI-MS: 242.1 (100%) [M+H]+, 264.0 (5.6%) [M+Na]+;
HRMS (APCI): m/z = 242.0793 ([M+H] +, calc. 242.0787).
methyl 3-(4-oxo-3,4-dihydropyridin-1(2H)-yl)benzoate (2m): Yield:
1
26.3 mg, 0.114 mmol, 38%, yellow oil; Rf = 0.14 (cHex/EtOAc = 2:3); H-
NMR, COSY (400 MHz, Chloroform-d) δ 7.79 (dt, J = 8.0, 1.2 Hz, 1H, H4’),
7.75 (dd, J = 2.6, 1.2 Hz, 1H, H2’), 7.46 (d, J = 7.8, 1H, H2), 7.45 (t, J =
8.0, 1H, H5’), 7.28 (ddd, J = 8.0, 2.6, 1.2 Hz, 1H, H6’), 5.26 (d, J = 7.8 Hz,
1H, H3), 4.03 (dd, J = 8.1, 7.1 Hz, 2H, H6), 3.92 (s, 3H, CH3), 2.67 (dd, J
= 8.1, 7.1 Hz, 2H, H5); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d)
δ 192.02 (C4), 166.38 (COOMe), 149.08 (C2), 145.30 (C1’), 131.75 (C3’),
129.88 (C5’), 125.22 (C4’), 122.24 (C6’), 118.93 (C2’), 103.00 (C3), 52.54
(CH3), 47.58 (C6), 36.02 (C5); IR: 1718, 1648, 1570, 1306, 1262, 1242,
1219, 1177, 1108, 755; ESI-MS: 232.1 (100%) [M+H]+, 254.1 (30.2%)
[M+Na]+, 485.1 (18.6%) [2M+Na]+; HRMS (ESI): m/z = 232.0971 ([M+H] +,
calc. 232.0968).
1-(4-nitrophenyl)-2,3-dihydropyridin-4(1H)-one (2i): Yield: 21.6 mg,
0.099 mmol, 33%, yellow solid; Rf = 0.26 (cHex/EtOAc = 1:4); mp: 125–
135 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 8.30–8.22 (m, 2H, H3’,
H5’), 7.52 (d, J = 8.0 Hz, 1H, H2), 7.20–7.13 (m, 2H, H2’, H6’), 5.40 (d, J
= 8.0 Hz, 1H, H3), 4.11–4.06 (m, 2H, H6), 2.76–2.69 (m, 2H, H5); 13C-
NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 191.96 (C4), 149.75 (C1’),
146.99 (C2), 143.19 (C4’), 125.86 (C3’, C5’), 116.84 (C2’, C6’), 105.71
(C3), 47.22 (C6), 36.04 (C5); IR: 1655, 1573, 1501, 1310, 1284, 1221,
1181, 1113, 854, 751; ESI-MS: 219.1 (100%) [M+H]+. The analytical data
are consistent with those reported in the literature.[25]
3-(4-oxo-3,4-dihydropyridin-1(2H)-yl)benzonitrile (2n): Yield: 23.7 mg,
0.120 mmol, 40%, yellow solid; Rf = 0.11 (cHex/EtOAc = 2:3); mp: 126.1–
1
130.0 °C; H-NMR, COSY (400 MHz, Chloroform-d) δ 7.54–7.45 (m, 1H,
H5‘), 7.42–7.38 (m, 2H, H2, H4‘), 7.36–7.30 (m, 2H, H2‘, H6‘), 5.30 (d, J =
7.9 Hz, 1H, H3), 4.05–3.97 (m, 2H, H6), 2.72–2.66 (m, 2H, H5); 13C-NMR,
HSQC, HMBC (101 MHz, Chloroform-d) δ 191.82 (C4), 148.06 (C2),
145.70 (C1‘), 130.76 (C5‘), 127.34 (C4‘), 122.01 (C6‘), 120.91 (C2‘),
118.16 (CN), 113.89 (C3‘), 104.21 (C3), 47.38 (C6), 35.99 (C5); IR: 2230,
1647, 1570, 1490, 1464, 1311, 1277, 1225, 1178, 1112, 796; ESI-MS:
N-methyl-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)benzamide (2j): Yield:
34.6 mg, 0.150 mmol, 50%, yellow solid; Rf = 0.19 (EtOAc/MeOH = 10:1);
mp: 177.4–178.8 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.85–
7.79 (m, 2H, H3‘, H5‘), 7.46 (d, J = 7.8 Hz, 1H, H2), 7.12–7.07 (m, 2H, H2‘,
H6‘), 6.58 (q, J = 4.8 Hz, 1H, NH), 5.25 (d, J = 7.8 Hz, 1H, H3), 4.03–3.98
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
199.1 (100%) [M+H]+, 221.0 (9.2%) [M+Na]+; HRMS (APCI): m/z =
199.0871 ([M+H] +, calc. 199.0866).
+, 485.2 (54%) [2M+Na] +; HRMS (ESI): m/z = 232.0970 ([M+H]+, calc.
232,0968).
1-phenylquinolin-4(1H)-one (2o): Yield: 58.4 mg, 0.264 mmol, 88%,
colorless solid; Rf = 0.07 (cHex/EtOAc = 2:3); mp: 124.5–126.2 °C; 1H-
NMR, COSY (400 MHz, Chloroform-d) δ 8.43 (dd, J = 8.1, 1.6 Hz, 1H, H5),
7.61–7.51 (m, 4H, H2, H3’, H4’, H5’), 7.46 (ddd, J = 8.6, 7.0, 1.6 Hz, 1H,
H7), 7.39–7.35 (m, 2H, H2’, H6’), 7.32 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H, H6),
7.00–6.96 (m, 1H, H8), 6.33 (d, J = 7.8 Hz, 1H, H3); 13C-NMR, HSQC,
HMBC (101 MHz, Chloroform-d) δ 178.31 (C4), 142.80 (C2), 141.37,
141.35 (C8a, C1’), 131.90 (C7), 130.37 (C3’, C5’), 129.57 (C4’), 127.60
(C2’, C6’), 126.59 (C4a), 126.56 (C5), 123.92 (C6), 117.36 (C8), 110.22
(C3); IR: 1626, 1589, 1550, 1493, 1479, 1465, 1365, 1290, 1237, 769, 704;
ESI-MS: 222.1 (100%) [M+H]+, 465.2 (8.1%) [2M+Na]+. The analytical data
are consistent with those reported in the literature.[26]
1-(3,5-dimethylphenyl)-2,3-dihydropyridin-4(1H)-one (2s): Yield: 35.2
mg, 0.175 mmol, 58%, yellow oil; Rf = 0.18 (cHex/EtOAc = 2:3); 1H-NMR,
COSY (400 MHz, Chloroform-d) δ 7.44 (d, J = 7.7 Hz, 1H, H2), 6.82–6.80
(m, 1H, H4’), 6.75–6.72 (m, 2H, H2’, H6’), 5.21 (d, J = 7.7 Hz, 1H, H3),
3.99 (dd, J = 8.1, 7.1 Hz, 2H, H6), 2.64 (dd, J = 8.1, 7.1 Hz, 2H, H5), 2.34
(s, 6H, 2 x CH3); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ
192.11 (C4), 149.94 (C2), 145.23 (C1’), 139.52 (C3’, C5’), 126.24 (C4’),
116.22 (C2’, C6’), 101.64 (C3), 47.72 (C6), 36.01 (C5), 21.51 (2 x CH3);
IR: 1648, 1606, 1573, 1474, 1328, 1306, 1235, 1192, 1177, 840; ESI-MS:
202.1 (100%) [M+H]+. The analytical data are consistent with those
reported in the literature.[10o]
methyl 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate (2t):
Yield: 20.9 mg, 0.0904 mmol, 30%, yellow oil; Rf = 0.14 (EtOAc = 100%);
1H-NMR, COSY (400 MHz, Chloroform-d) δ 8.51 (s, 1H, H2), 7.48–7.41
(m, 2H, H3’, H5’), 7.31–7.27 (m, 1H, H4’), 7.25–7.21 (m, 2H, H2’, H6’),
4.12–4.07 (m, 2H, H6), 3.80 (s, 3H, OCH3), 2.76–2.70 (m, 2H, H5); 13C-
NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 186.93 (C4), 165.90
(COOMe), 156.60 (C1), 144.36 (C1’), 130.01 (C3’, C5’), 126.73 (C4’),
119.81 (C2’, C6’), 103.57 (C3), 51.70 (OCH3), 48.27 (C6), 36.39 (C5); IR:
1720, 1666, 1571, 1494, 1386, 1323, 1257, 1202, 1147, 1071, 762; ESI-
MS: 232.1 (100%) [M+H]+, 254.1 (36.4%) [M+Na]+, 485.2 (68.1%)
[2M+Na]+; HRMS (ESI): m/z = 232.0972 ([M+H] +, calc. 232.0968).
1-(naphthalen-1-yl)quinolin-4(1H)-one (2p): Yield: 72.0 mg, 0.265 mmol,
89%, yellow solid; Rf = 0.15 (cHex/EtOAc = 2:3); mp: 174.2–178.3 °C; 1H-
NMR, COSY (400 MHz, Chloroform-d) δ 8.54–8.44 (m, 1H, H5), 8.07 (dt,
J = 8.4, 1.0 Hz, 1H, H4’), 8.00 (dt, J = 8.2, 1.0 Hz, 1H, H5’), 7.64 (dd, J =
8.4, 7.3 Hz, 1H, H3’), 7.60 (d, J = 7.7 Hz, 1H, H2), 7.59–7.54 (m, 2H, H2’,
H6’), 7.42 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, H7’), 7.37–7.27 (m, 3H, H6, H7,
H8’), 6.70–6.64 (m, 1H, H8), 6.41 (d, J = 7.7 Hz, 1H, H3); 13C-NMR, HSQC,
HMBC (101 MHz, Chloroform-d) δ 178.48 (C4), 143.35 (C2), 141.96 (C8a),
137.45 (C1’), 134.64 (C4a’), 132.10 (C7), 130.41 (C4’), 130.09 (C8a’),
128.71 (C5’), 128.14 (C7’), 127.37 (C6’), 126.54 (C4a), 126.51 (C5),
126.14 (C2’), 125.83 (C3’), 123.95 (C6), 122.16 (C8’), 117.63 (C8), 110.41
(C3); IR: 1624, 1606, 1590, 1551, 1478, 1395, 1365, 1289, 773, 729; ESI-
MS: 272.1 (100%) [M+H]+, 565.3 (11.1%) [2M+Na]+; HRMS (ESI): m/z =
272.1073 ([M+H] +, calc. 272.1070).
methyl
7-oxo-4-phenyl-4,5,6,7-tetrahydro-1,4-oxazepine-2-
carboxylate (2t’): Yield: 12.5 mg, 0.0506 mmol, 17%, yellow oil; Rf = 0.58
1
(cHex/EtOAc = 2:3); H-NMR, COSY (400 MHz, Chloroform-d) δ 7.62 (s,
1H, H3), 7.41–7.36 (m, 2H, H3’, H5’), 7.20–7.15 (m, 1H, H4’), 7.14–7.10
(m, 2H, H2’, H6’), 4.11–4.07 (m, 2H, H5), 3.81 (s, 3H, OCH3), 3.12–3.09
(m, 2H, H6); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) 169.44
(C7), 164.38 (COOMe), 145.77 (C1’), 129.86 (C3’, C5’), 128.39 (C3),
125.00 (C4’), 119.82 (C2’, C6’), 119.69 (C2), 52.32 (OCH3), 47.69 (C5),
35.41 (C6); IR: 1756, 1709, 1645, 1595, 1495, 1266, 1242, 1216, 1145,
756; ESI-MS: 248.1 (100%) [M+H]+, 270.1 (28.0%) [M+Na]+, 517.2
(49.5%) [2M+Na]+; HRMS (ESI): m/z = 248.0920 ([M+H]+, calc. 248.0917).
1-(naphthalen-1-yl)-2,3-dihydropyridin-4(1H)-one (2q): Yield: 27.5 mg,
0.123 mmol, 41%, brown solid; Rf = 0.20 (cHex/EtOAc = 2:3); mp: 90.0–
98.9 °C; 1H-NMR, COSY (400 MHz, Chloroform-d) δ 8.05–8.01 (m, 1H,
H8’), 7.94–7.91 (m, 1H, H5’), 7.82 (dt, J = 8.4, 1.1 Hz, 1H, H2’), 7.65–7.52
(m, 2H, H6’, H7’), 7.48 (dd, J = 8.4, 7.3 Hz, 1H, H3’), 7.33 (d, J = 7.6 Hz,
1H, H2), 7.30 (dd, J = 7.3, 1.1 Hz, 1H, H4’), 5.27 (d, J = 7.6 Hz, 1H, H3),
3.99 (t, J = 7.6 Hz, 2H, H6), 2.92–2.63 (br m, 2H, H5); 13C-NMR, HSQC,
HMBC (101 MHz, Chloroform-d) δ 192.10 (C4), 153.81 (C2), 142.73 (C1’),
134.83 (C4a’), 128.97 (C8a’), 128.85 (C5’), 127.88 (C2’), 127.27, 126.89
(C6’, C7’), 125.73 (C3’), 122.45 (C8’), 121.77 (C4’), 101.26 (C3), 51.10
(C6), 36.57 (C5); IR: 1644, 1585, 1570, 1395, 1300, 1221, 1173, 1111,
799, 774; ESI-MS: 224.1 (100%) [M+H]+, 246.1 (10.2%) [M+Na]+, 469.1
(12.5%) [2M+Na]+; HRMS (ESI): m/z = 224.1071 ([M+H]+, calc. 224.1070).
Gram scale procedure for the photoredox-catalyzed aerobic
dehydrogenation: A 30 mL glass vial was charged with 1a (1.15 g, 6.59
mmol, 1.00 eq.), rhodamine 6G (7) (0.0659 mmol, 1 mol%) and anhydrous
DMF (22.0 mL). The mixture was stirred until rhodamine 6G was
completely dissolved. A steady stream of oxygen was slowly bubbled
through the solution (one bubble per second) using a disposable glass
Pasteur pipet (see SI for irradiation setup). The mixture was stirred under
irradiation with green LED stripes, until the starting material 1a was almost
consumed completely as judged by TLC and LC-MS analysis (careful
monitoring the reaction progress is recommended to avoid over-oxidation).
Water (50 mL) was added and the mixture was extracted with Et2O (4 x 50
mL) to remove most of DMF. The organic phases were combined, dried
over Na2SO4, filtered and the solvent was removed in vacuo. The crude
product was purified by column chromatography (SiO2, cHex/EtOAc = 2:3)
to yield 2a (680.2 mg, 3.927 mmol, 60%).
1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-dihydropyridin-4(1H)-one
(2r): Yield: 24.6 mg, 0.106 mmol, 35%, orange needles; Rf = 0.24
(cHex/EtOAc = 1:4); mp: 163.3–170.9 °C; 1H-NMR, COSY (400 MHz,
Chloroform-d) δ 7.33 (d, J = 7.7 Hz, 1H, H2), 6.85 (d, J = 8.7 Hz, 1H, H8’),
6.62 (d, J = 2.8 Hz, 1H, H5’), 6.59 (dd, J = 8.7, 2.8 Hz, 1H, H7’), 5.17 (d, J
= 7.7 Hz, 1H, H3), 4.30–4.21 (m, 4H, H2’, H3’), 3.95–3.88 (m, 2H, H6),
2.67–2.58 (m, 2H, H5); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-
d) δ 191.96 (C4), 150.30 (C2), 144.12 (C4a’), 140.96 (C8a’), 139.63 (C6’),
118.03 (C8’), 112.09 (C7’), 108.31 (C5’), 101.39 (C3), 64.67, 64.40 (C2’,
C3’), 48.27 (C6), 36.04 (C5); IR: 1627, 1576, 1506, 1316, 1284, 1254,
1213, 1067, 894, 866; ESI-MS: 232.1 (100%) [M+H]+, 254.2 (26%) [M+Na]
General procedure for the one-pot synthesis of azocinones: The
synthesis was performed according to the general procedure of the
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
dehydrogenation, with the following exception: After irradiation the reaction
vessel was flushed with argon for 2 minutes, followed by addition of
anhydrous ACN (1.00 mL) and the respective acetylene ester 11 (0.900
mmol, 3.00 eq.). The reaction mixture was heated at 90 °C in an oil bath
for 20 h, followed by the usual work-up as described above.
(C2), 142.84 (d, J = 2.9 Hz, C1’), 133.97 (C4), 132.79 (C5), 125.34 (d, J =
8.2 Hz, C2’, C6’), 116.73 (d, J = 22.8 Hz, C3’, C5’), 97.33 (C3), 52.78 (CH3),
51.87 (CH3), 47.93 (C8), 38.49 (C7); IR: 1702, 1609, 1585, 1506, 1434,
1230, 1201, 1158, 1090, 1057, 730; ESI-MS: 302.1 (41.1%) [M−OMe]+,
334.1 (100%) [M+H]+, 356.1 (61.4%) [M+Na]+, 689.3 (62.7%) [2M+Na]+;
HRMS (ESI): m/z = 334.1086 ([M+H] +, calc. 334.1085).
dimethyl
(2E,4E)-6-oxo-1-phenyl-1,6,7,8-tetrahydroazocine-3,4-
dicarboxylate (12a): Yield: 58.2 mg, 0.185 mmol, 62%, orange resin; Rf
= 0.50 (cHex/EtOAc = 2:3); 1H-NMR, COSY (400 MHz, Chloroform-d) δ
7.63 (s, 1H, H2), 7.39–7.32 (m, 2H, H3’, H5’), 7.24–7.19 (m, 1H, H4’),
7.14–7.09 (m, 2H, H2’, H6’), 6.63 (s, 1H, H5), 4.35 (s, 2H, H8), 3.79 (s, 3H,
4-CO2CH3), 3.62 (s, 3H, 3-CO2CH3), 2.56 (s, 2H, H7); 13C-NMR, HSQC,
HMBC (101 MHz, Chloroform-d) δ 205.67 (C6), 168.61 (3-CO), 168.27 (4-
CO), 146.49 (C1’), 144.79 (C2), 134.12 (C4), 132.64 (C5), 129.83 (C3’,
C5’), 126.39 (C4’), 122.84 (C2’, C6’), 97.23 (C3), 52.71 (4-CO2CH3), 51.78
(3-CO2CH3), 47.35 (C8), 38.72 (C7); IR: 1726, 1705, 1610, 1582, 1494,
1435, 1239, 1203, 1091, 1057; ESI-MS: 284.1 (39.5%) [M−OMe]+, 316.1
(100%) [M+H]+, 338.1 (44.8%) [M+Na]+, 653.3 (39.3%) [2M+Na]+; HRMS
(ESI): m/z = 338.0994 ([M+Na]+, calc. 338.0999).
diethyl
(2E,4E)-6-oxo-1-phenyl-1,6,7,8-tetrahydroazocine-3,4-
dicarboxylate (12e): Yield: 52.4 mg, 0.153 mmol, 51%, orange resin; Rf
= 0.59 (cHex/EtOAc = 2:3); 1H-NMR, COSY (400 MHz, Chloroform-d) δ
7.65 (s, 1H, H2), 7.40–7.34 (m, 2H, H3’, H5’), 7.25–7.20 (m, 1H, H4’),
7.15–7.11 (m, 2H, H2’, H6’), 6.63 (s, 1H, H5), 4.57–3.99 (m, 2H, H8), 4.27
(q, J = 7.1 Hz, 2H, OCH2CH3), 4.10 (q, J = 7.1 Hz, 2H, OCH2CH3), 2.58 (br
m, 2H, H7), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.20 (t, J = 7.1 Hz, 3H,
OCH2CH3); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 205.89
(C6), 168.32 (CO2Et), 167.92 (CO2Et), 146.60 (C1’), 144.65 (C2), 134.72
(C4), 132.26 (C5), 129.87 (C3’, C5’), 126.30 (C4’), 122.82 (C2’, C6’), 97.79
(C3), 61.70 (OCH2CH3), 60.62 (OCH2CH3), 47.37 (C8), 38.90 (C7), 14.35
(OCH2CH3), 14.29 (OCH2CH3); IR: 1702, 1608, 1578, 1493, 1364, 1230,
1197, 1092, 1054, 1030, 757, 697; ESI-MS: 298.1 (45.7%) [M−OEt]+,
344.2 (100%) [M+H]+, 709.4 (44.8%) [2M+Na]+; HRMS (ESI): m/z =
344.1496 ([M+H] +, calc. 344.1492).
dimethyl
(2E,4E)-6-oxo-1-(p-tolyl)-1,6,7,8-tetrahydroazocine-3,4-
dicarboxylate (12b): Yield: 56.6 mg, 0.172 mmol, 57%, orang resin; Rf =
0.57 (cHex/EtOAc = 2:3); 1H-NMR, COSY (400 MHz, Chloroform-d) δ 7.61
(s, 1H, H2), 7.18–7.15 (m, 2H, H3’, H5’), 7.03–6.98 (m, 2H, H2’, H6’), 6.62
(s, 1H, H5), 3.92–3.67 (br m, 2H, H8), 3.81 (s, 3H, OCH3), 3.63 (s, 3H,
OCH3), 2.55 (br m, 2H, H7), 2.33 (s, 3H, ArCH3); 13C-NMR, HSQC, HMBC
(101 MHz, Chloroform-d) δ 205.80 (C6), 168.72 (CO2Me), 168.44 (CO2Me),
145.18 (C2), 144.19 (C1’), 136.52 (C4’), 134.27 (C4), 132.43 (C5), 130.40
(C3’, C5’), 123.09 (C2’, C6’), 96.75 (C3), 52.75 (OCH3), 51.79 (OCH3),
47.58 (C8), 38.59 (C7), 20.95 (ArCH3); IR: 1726, 1704, 1581, 1511, 1434,
1305, 1238, 1202, 1090, 1057; ESI-MS: 298.1 (44.1%) [M−OMe]+, 330.2
(100%) [M+H]+, 352.2 (20.5%) [M+Na]+, 681.3 (46.7%) [2M+Na]+; HRMS
(ESI): m/z = 352.1156 ([M+Na] +, calc. 352.1155).
Acknowledgments
We thank Dr. Johannes C. Liermann (Mainz) for helpful
discussions and measurements of NMR spectra, Dr. Christopher
Kampf (Mainz) for mass spectrometry, and Prof. Jurij Svete
(Ljubljana) for the helpful discussion. This work was supported by
the LESSING initiative at JGU and by the Rhineland Palatinate
Natural Products Research Center.
dimethyl
(2E,4E)-1-(3-methoxyphenyl)-6-oxo-1,6,7,8-
tetrahydroazocine-3,4-dicarboxylate (12c): Yield: 47.9 mg, 0.139 mmol,
46%, orange resin; Rf = 0.44 (cHex/EtOAc = 2:3); 1H-NMR, COSY (400
MHz, Chloroform-d) δ 7.65 (s, 1H, H2), 7.27 (t, J = 8.2 Hz, 1H, H5’), 6.76
(ddd, J = 8.2, 2.3, 0.8 Hz, 1H, H4’), 6.71 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H,
H6’), 6.67–6.60 (m, 2H, H5, H2’), 4.34 (br m, 2H, H8), 3.81 (s, 3H,
CO2CH3), 3.80 (s, 3H, ArOCH3), 3.64 (s, 3H, CO2CH3), 2.57 (br m, 2H,
H7); 13C-NMR, HSQC, HMBC (101 MHz, Chloroform-d) δ 205.62 (C6),
168.63 (CO2Me), 168.32 (CO2Me), 160.70 (C3’), 147.71 (C1’), 144.67 (C2),
134.25 (C4), 132.65 (C5), 130.61 (C5’), 114.93 (C6’), 111.53 (C4’), 109.07
(C2’), 97.37 (C3), 55.61 (ArOCH3), 52.77 (CO2CH3), 51.85 (CO2CH3),
47.36 (C8), 38.86 (C7); IR: 1725, 1705, 1582, 1491, 1435, 1330, 1237,
1194, 1172, 1090, 1051, 777; ESI-MS: 314.1 (62.7%) [M−OMe]+, 346.2
(100%) [M+H]+, 368.1 (20.5%) [M+Na]+, 713.3 (26.8%) [2M+Na]+; HRMS
(APPI): m/z = 346.1290 ([M+H] +, calc. 346.1285).
Keywords: Photocatalysis • photooxidation • sustainable
chemistry • nitrogen heterocycles • ring expansion
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
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10.1002/ejoc.201900584
European Journal of Organic Chemistry
ARTICLE
Entry for the Table of Contents (Please choose one layout)
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FULL PAPER
Photoredox catalysis*
Adrian Sevenich, Paulina Sophie Mark,
Torsten Behrendt, and Till Opatz*
Page No. – Page No.
Synthesis of 2,3-Dihydro-4-Pyridones,
4-Quinolones and 2,3-Dihydro-4-
Azocinones by Visible-Light
Photocatalytic Aerobic
A protocol for the synthesis of three types of N-heterocycles was developed. Cyclic
enaminones were prepared under eco-friendly conditions by photocatalytic
dehydrogenation using rhodamine 6G as inexpensive photocatalyst and oxygen as
the terminal oxidant. The method was extended to access azocinones via a [2+2]
cycloaddition/ring-expansion sequence in a one-pot procedure.
Dehydrogenation
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.