Photoinduced iodine-mediated tandem dehydrogenative Povarov cyclisation/C-H oxygenation reactions

Article abstract of DOI:10.1039/d0ob01494j

We report metal-free, photoinduced aerobic tandem dehydrogenative Povarov cyclisation/Csp3-H oxygenation reactions between N-aryl glycine esters and α-substituted styrenes, which efficiently lead to 4,4-disubstituted dihydroquinoline-3-ones under mild conditions. The reactions are mediated by iodine along with visible light irradiation, which allows for the in situ generation of the essential Br?nsted acid HI, to catalyse the key imine [4+2]-cycloaddition.

Full text of DOI:10.1039/d0ob01494j

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: E. Schendera, A.
Villinger and M. Brasholz, Org. Biomol. Chem., 2020, DOI: 10.1039/D0OB01494J.
Volume 15
Number 47
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
21
December 2017
Pages 9945-10124
Organic &
Biomolecular
Chemistry
rsc.li/obc
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
single cell transcriptome in vivo analysis (TIVA)
rsc.li/obc

Page 1 of 5
O rP gl ea na is ce &d Bo i on mo to al e dc juu l sa tr mC haer mg i ins ts ry
View Article Online
DOI: 10.1039/D0OB01494J
Paper
Photoinduced iodine-mediated tandem dehydrogenative Povarov
cyclisation / C−H oxygenation reactions
a
a
a
Eva Schendera, Alexander Villinger, and Malte Brasholz*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report metal-free, photoinduced aerobic tandem dehydrogenative
Povarov cyclisation / Csp −H oxygenation reactions between N-aryl
glycine esters and α-substituted styrenes, which efficiently lead to 4,4-
disubstituted dihydroquinoline-3-ones under mild conditions. The
reactions are mediated by iodine along with visible light irradiation,
which allows for the in situ generation of the essential Brønsted acid HI, regioselective Povarov cyclisations with indoles, and efficient
to catalyse the key imine [4+2]-cycloaddition.
We recently reported photoinduced and transition metal-free
dehydrogenative Povarov reactions, mediated by iodine and
visible light under aerobic conditions (Scheme 1c, left).7 The
initial dehydrogenation of N-aryl glycine esters was followed by
3
a,b
aromatization of the intermediate cycloadducts under the
aerobic conditions led to tetracyclic indolo[3,2-c]quinoline
products in high yields. In these reactions, atomic iodine,
The direct oxidative C−H functionalisation of organic com-
pounds is a highly attractive strategy for sustainable and target-
oriented synthesis, and versatile new synthetic methods have
2
generated by photolysis of a substoichiometric quantity of I ,
effected six consecutive hydrogen abstractions, and the in situ-
generated hydrogen iodide (HI) acted as the Brønsted acid
catalyst for the key imine [4+2]-cycloaddition. Herein, we report
1
3
emerged in recent years. As an example, the Csp −H function-
nalisation of amines has attracted much attention, and it has
extensively been utilized for the synthesis of polysubstituted
amines as well as in the construction of N-heterocyclic
compounds. One such protocol is the dehydrogenative Povarov
reaction between N-aryl glycines and alkenes (Scheme 1). In
these reactions, an amine-to-imine oxidation precedes a pivotal
imine [4+2]-cycloaddition, which can be catalysed by a wide
2 2
that the same metal-free system of I and O , under blue light
irradiation, also efficiently mediates tandem dehydrogenative
3
Povarov cyclisation / Csp −H oxygenation reactions between N-
aryl glycines and 1,1-disubstituted alkenes (Scheme 1c, right).
2
range of Brønsted or Lewis acids, and the consecutive oxidative
aromatization leads to substituted quinoline products.
Dehydrogenative Povarov reactions have been achieved
utilizing metal catalysts like Cu(I) and Cu(II) salts as well as Fe(II)
and Au(I) and Au(III) complexes along with DDQ, organic
3
peroxides or O
2
as the stoichiometric oxidants (Scheme 1a).
Double dehydrogenative variants of the Povarov reaction,
including the parallel oxidation of an alkane as the precursor to
4
the alkene 2π component, have also been introduced lately, as
5
well as first photoredox catalytic protocols. In 2017, Jia and co-
workers reported a dehydrogenative Povarov reaction between
N-aryl glycines and α-substituted styrenes, which was
3
accompanied by a subsequent Csp −H oxygenation. Utilizing a
dual catalytic system of a Cu(II) salt along with an aminium
radical cation salt in the presence of oxygen, 4,4-disubstituted
quinolone-3-ones could be accessed by these tandem
6
functionalisations (Scheme 1b).
a.University of Rostock, Institute of Chemistry, Albert-Einstein-Str. 3A, 18055
Scheme 1. Methods for dehydrogenative Povarov reactions.
Rostock, Germany. Email: malte.brasholz@uni-rostock.de
Electronic Supplementary Information (ESI) available: Full experimental details and
compound characterization data. See DOI: 10.1039/x0xx00000x
Please do not adjust margins

O rP gl ea na is ce &d Bo i on mo to al e dc juu l sa tr mC haer mg i ins ts ry
Page 2 of 5
COMMUNICATION
Journal Name
9
We initially observed that reacting N-p-toluidinyl glycine ester of 23-33% after 48 h. In addition, N-Phenyl glycine 1f as well as
View Article Online
1
1
a
with α-methylstyrene (2a) in MeCN, in the presence of the 4-trifluoromethylphenyl and the 3-DpOyrI:id10y.l10d3e9r/Div0aOtiBv0e1s4914gJ
0 mol-% of iodine, under O atmosphere and with blue light and 1h were unsuitable reaction partners. While compound 1f
2
irradiation, led to full conversion of glycine ester 1a, while the partially underwent aromatic iodination under the reaction
4
1
,4-disubstituted dihydroquinoline-3-one 3a was produced in conditions, the electron-deficient amines 1g and 1h did not
5% yield, conversion of α-methylstyrene (2a) being incomplete undergo the initial dehydrogenation to the corresponding
at 73% (Table 1, entry 1). Increasing quantities of I
prolonged reaction times both improved the yield of 3a (entries limonene (
−5), even though an extended reaction time with only 20 mol-
of iodine did not lead to a significant increase in yield of 3a
despite complete conversion of both substrates, 1a and 2a
entry 3). Using 50 mol-% of I under continuous irradiation for
8 h furnished the desired product 3a in 74% isolated yield
2
and imines. Further, the use of non-conjugated alkenes like e.g.
4
) was unsuccessful.
2
%
(
4
2
(entry 5). Alternative iodine sources such as N-iodosuccinimide
(NIS) and iodine monochloride (ICl) also induced the
dehydrogenative Povarov cyclisation / oxygenation reaction
between 1a
,
2a and O
2
, however, with lesser efficiency (entries
8
6
and 7). Tetramethylammonium dichloroiodate was unsui-
table as promoter, leaving glycine ester 1a as well as styrene
derivative 2a fully intact (entry 8). Using bromine or NBS at
5
0 mol-% each, no or hardly any conversion of glycine ester 1a
occurred (entries 9 and 10), but these reagents effected the full
conversion of α-methylstyrene (2a) into a mixture of unwanted
brominated products.
Table 1. Reaction optimization.
reagent
conv. 1a
[%]
conv. 2a
[%]
yield 3a
[%]
#
time [h]
[a]
[a]
[b]
(mol-%)
1
2
3
4
5
6
7
8
9
I
I
I
I
I
2
2
2
2
2
(10)
(20)
(20)
(50)
(50)
24
24
48
24
48
48
48
48
48
48
100
100
100
100
100
100
0
73
81
15
50
54
Figure 1. Reaction scope. Yields after chromatography. Conditions:
1 (0.20 mmol),
2
(0.10 mmol), I (50 mol-%), MeCN (0.03 M), O , hv (450±50) nm, r.t., 48 h.
2
2
100
85
The diminished yields in the reactions leading to compounds 3g
and 3h can partially be attributed to the fact that conversion of
53
74 (74 [c]
100
100
100
0
)
the alkene component
2 was incomplete even after a reaction
NIS (50)
ICl (50)
50
44
0
time of 48 h, evidently as a result of a less efficient and
somewhat slower [4+2]-cycloaddition. In addition, the 1,1-
diaryl-substituted ethenes partially underwent oxidative C,C-
cleavage to the corresponding benzophenones which could be
isolated as byproducts in these reactions. Another origin of the
decreased reaction selectivity in some cases became evident in
+
-
Me
4
N ICl
Br (50)
NBS (50)
2
(50)
0
2
0
100
100
0
10
12
0
Reactions were performed on 0.10 mmol scale of 2a, irradiation with 36 W blue compact
fluorescent lamps (CFL), λ = (450±50) nm. [a] Conversion determined by H NMR spectroscopic
analysis. [b] Yield determined by H NMR spectroscopy against CH
Yield of isolated product after chromatography.
1
1
2 2
Br as internal standard. [c]
reaction of p-anisidinyl glycine ester 1i with α-methylstyrene 2a
.
While 3,4-dihydroquinoline-2-carboxy-late 3m was isolated in a
moderate yield of 28%, the rearranged 4-methyl-3-
phenylquinoline 5 was generated in 23% yield (Scheme 2a). The
same rearrangement was observed in several other reactions,
however, the corresponding products were formed in small
quantities (<5%) only. Their formation can be rationalised by the
A number of 3,4-dihydroquinoline-3-ones
synthesized under the optimized reaction conditions (Figure 1).
Utilizing p-toluidinyl glycine ester 1a in combination with
various α-alkylstyrenes, full conversion of the alkenes
3 could readily be
2 was
observed in all cases and products 3a 3f could be obtained in
-
yields ranging from 59-74%. 1,1-Diarylethenes also were
suitable 2π-components, leading to the 4,4-diarylated
compounds 3g and 3h with 47% and 48% yield, respectively.
Upon variation of the N-aryl glycine ester component, we found
that both donor and acceptor substituents on the aromatic ring
diminished the product selectivity, and as a consequence, the
generation of an intermediate azaallyl radical
6 followed by an
intramolecular 1,2-aryl shift via the spirocyclohexadienyl radical
7
and a succeeding benzylic radical
8
which undergoes a final
In addition to 1,1-disubstituted
9) could also be employed in the
6,10
dehydrogenation to
styrenes, β-methylstyrene (
5.
dehydrogenative Povarov reaction with glycine ester 1a, leading
oxygenated cycloadducts 3i-3l were isolated in moderate yields
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
O rP gl ea na is ce &d Bo i on mo to al e dc juu l sa tr mC haer mg i ins ts ry
Journal Name
COMMUNICATION
·
to 3-methyl-4-phenyl-substituted quinoline carboxylate 10 in HI. Another hydrogen abstraction from 19 by I leads to azaallyl
6
View Article Online
DOI: 10.1039/D0OB01494J
2
5% yield (Scheme 2b). 2,3-Dihydrofuran (11) was another radical 20, which adds a second molecule of O . A further chain
suitable 2π-component, to give the δ-lactone-fused quinoline propagation step between peroxyl radical 21 and glycine ester
after cycloaddition, acid-induced ring-opening and gives hydroperoxide 22, which, under elimination of water, is
converted into product . Overall, the Brønsted acid catalyst HI,
1
2
1
1
1,4d
intramolecular transesterification (Scheme 2c).
3
which drives the [4+2]-cycloaddition, is generated in situ by this
a)
method, while five H-abstraction steps are effected by atomic
2
iodine. Since just 50 mol-% of I are employed, corresponding to
one equivalent of reactive iodine atoms, the reaction can be
classified as catalytic in iodine. This is also confirmed by the
entries 6 and 7 in Table 1, where NIS and ICl were employed as
promoters in 50 mol-% quantity each.
a)
b)
b)
c)
c)
d)
Scheme 2. a) Reaction leading to the rearranged 3,4-disubstituted quinoline
5. b)
Reaction between 1a and β-methylstyrene (
9). c) Reaction between 1a and 2,3-
dihydrofuran (11).
Control experiments aimed at elucidating the reaction
mechanism are depicted in Scheme 3. When N-p-toluidinyl
glycine ester 1a was irradiated alone, under the typical reaction
conditions, imine 13a was formed quantitatively within 48 h
Scheme 3. Control experiments.
(Scheme 3a). The reaction between imine 13a and α-
methylstyrene (2a) in the presence of light, O and iodine
2
produced compound 3a in 74% yield, just as observed when
employing glyine ester 1a (Scheme 3b). No reaction occurred in
the absence of I , O or visible light (Scheme 3c). When the
2 2
reference reaction between 1a and 2a was conducted in the
presence of one equivalent of TEMPO, radical adduct 14 was
formed as confirmed by ESI-TOF mass spectrometry (Scheme
1
d). Consistent with the above observations and previous
6
,7a,12
reports,
we propose a reaction mechanism as shown in
Scheme 4. Photolysis of molecular iodine generates atomic
iodine, which abstracts a methylene hydrogen atom from
glycine ester
HI). Trapping of 15 with oxygen gives peroxyl radical 16, which
reacts with substrate in a chain propagation step, generating
hydroperoxide 17. Elimination of hydrogen peroxide (H
produces imine 13, which undergoes a Brønsted acid-catalysed
Povarov cyclisation with styrene derivative , mediated by the
in situ-generated HI. The HI catalyst can be reoxidised to I
1, to give α-amino radical 15 and hydrogen iodide
(
1
2 2
O )
2
by Scheme 4. Proposed reaction mechanism.
Cycloadduct 18 is dehydrogenated to 3,4-dihydro-
2
13
2
H O
2
.
quinoline intermediate 19 by atomic iodine, again generating
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

O rP gl ea na is ce &d Bo i on mo to al e dc juu l sa tr mC haer mg i ins ts ry
Page 4 of 5
COMMUNICATION
Journal Name
Chen and H. Liu, J. Org. Chem., 2009, 74, 5476-5480. d) M. J.
Conclusions
View Article Online
DOI: 10.1039/D0OB01494J
Alves, N. G. Azoia and A. G. Fortes, Tetrahedron, 2007, 63
,
Iodine, in the presence of oxygen and under visible light
irradiation, efficiently mediates the metal-free tandem
dehydrogenative
reaction between N-aryl glycine esters and styrenes, to afford
differentially substituted dihydroquinoline-3-ones in moderate
to high yields. A substoichiometric quantity of 50 mol-% of I
allows for the consecutive abstraction of five hydrogen atoms,
and thus the reaction can be regarded as catalytic in iodine.
Moreover, the essential Brønsted acid catalyst to mediate the
pivotal imine [4+2]-cycloaddition is readily generated in situ
during the course of the multistep reaction. Future
investigations are necessary to overcome intrinsic limitations of
the present method, such as the lack of reactivity of electron-
deficient N-arylglycine esters like 1g and 1h in the initial
dehydrogenation event.
7
2
27-734. e) D. Osborne and P. J. Stevenson, Tetrahedron Lett.,
002, 43, 5469-5470. f) E. Borrione, M. Prato, G. Scorrano, M.
3
Povarov cyclisation / Csp −H oxygenation
Stivanello and V. Lucchini, J. Heterocyclic Chem., 1988, 25
831-1835.
a) M. Ni, Y. Zhang, T. Gong and B. Feng, Adv. Synth. Catal.,
017, 359, 824-831. b) Z. Xie, J. Jia, X. Liu and L. Liu, Adv. Synth.
,
1
3
4
2
2
Catal., 2016, 358, 919-925. c) H. Richter and O. García
Mancheño, Org. Lett., 2011, 13, 6066-6069.
a) W. Jiang, S. Wan, Y. Su and C. Huo, J. Org. Chem., 2019, 84
,
8
232-8241. b) W. Jiang, Y. Wang, P. Niu, Z. Quan, Y. Su and C.
Huo, Org. Lett., 2018, 20, 4649-4653. c) C. Huo, F. Chen, Y.
Yuan, H. Xie and Y. Wang, Org. Lett., 2015, 17, 5028-5031. d)
C. Huo, H. Xie, F. Chen, J. Tang and Y. Wang, Adv. Synth. Catal.,
2
016, 358, 724-730. e) C. Huo, H. Xie, M. Wu, X. Jia, X. Wang,
F. Chen and J. Tang, Chem. Eur. J., 2015, 21, 5723-5726.
5
a) X. Yang, L. Li, Y. Zhang, J. Org. Chem., 2016, 81, 12433-
1
2442. b) Y. He, B. Yan, H. Tao, Y. Zhang, Y. Li, Org. Biomol.
Experimental
General procedure for the synthesis of compounds 3. In a
Chem., 2018, 16, 3816-3823.
X. Jia, W. Hou, Y. Shao, Y. Yuan, Q. Chen, P. Li, X. Liu and H. Ji,
Chem. Eur. J., 2017, 23, 12980-12984.
a) E. Schendera, L.-N. Unkel, Phung Phan H. Q., G. Salkewitz,
F. Hoffmann, A. Villinger and M. Brasholz, Chem. Eur. J.,
2020, 26, 269-274. b) For a review of I -mediated C−H
6
7
1
0 mL crimp cap vial, N-aryl glycine ester
and styrene derivative (typically 0.10 mmol) were dissolved in
MeCN (3.50 mL per 0.10 mmol of ). I (50 mol-%) was added,
the vial was sealed and fitted with an O -balloon (septum
1 (typically 0.20 mmol)
2
2
2
2
2
pierced by needle). The mixture was irradiated between two
blue CFL lamps (2×18 W, 450±50 nm) with rapid stirring for
functionalisation reactions, see: P. T. Parvatkar, R. Manetsch
and B. K. Banik, Chem. Asian J., 2019, 14, 6-30.
4
8 h. The mixture was poured into NaHCO
followed by extraction with EtOAc (3×). The combined organic
layers were dried with Na SO , filtered and evaporated to
dryness. Column chromatography (silica gel) furnished
product
3
aq. and Na
2
S
2
O
3
aq.
8
9
A. R. Hajipour, M. Arbabian and A. E. Ruoho, J. Org. Chem.,
2002, 67, 8622-8624.
CCDC 2022869 contains the supplementary crystallographic
data for compound 3l. These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
0 W.-T. Wei, F. Teng, Y. Li, R.-J. Song and J.-H. Li, Org. Lett.,
2
4
3
.
1
1
1
2
019, 21, 6285-6288.
1 C. Huo, Y. Yuan, M. Wu, X. Jia, X. Wang, F. Chen and J. Tang,
Angew. Chem. Int. Ed., 2014, 53, 13544-13547.
2 For a recent DFT study of the mechanism of the
dehydrogenative Povarov reaction of glycine derivatives,
see: D.-G. Zhou and P. Wang, New J. Chem., 2020, 44, 2833-
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
2
846.
The authors thank the University of Rostock for financing this
research.
1
3 G. Schmitz, Phys. Chem. Chem. Phys., 2001, 3, 4741-4746.
TOC graphic
Notes and references
1
Selected reviews: a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335-
3
2
44. b) S.-Y. Zhang, F.-M. Zhang and Y-Q. Tu, Chem. Soc. Rev.,
011, 40, 1937-1949. c) C. Zhang, C. Tang and N. Jiao, Chem.
Soc. Rev., 2012, 41, 3464-3484. d) S. A. Girard, T. Knauber and
C.-J. Li, Angew. Chem. Int. Ed., 2014, 53, 74-100. e) A. Batra, P.
Singh and K. N. Singh, Eur. J. Org. Chem., 2016, 4927-4947. f)
D. J. Abrams, P. A. Provencher and E. J. Sorensen, Chem. Soc.
Rev., 2018, 47, 8925-8967.
2
a) G. Bianchini, P. Ribelles, D. Becerra, M. T. Ramos and J. C.
Menéndez, Org. Chem. Front., 2016, 3, 412-422. b) J. McNulty,
R. Vemula, C. Bordón, R. Yolken and L. Jones-Brando, Org.
Biomol. Chem., 2014, 12, 255-260. c) H. Huang, H. Jiang, K.
Visible light and iodine mediate dehydrogenative imine [4+2]-
cycloaddition / C-H oxygenation reactions to furnish highly
functionalised 3-quinolones under metal-free conditions.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry