Fe(III)-catalyzed Oxidative Povarov Reaction with Molecular Oxygen Oxidant

Article abstract of DOI:10.1002/bkcs.12273

The synthesis of tetrahydroquinoline derivatives from dimethyl anilines and enamides has been developed by Fe(III)-phenanthroline complex under aerobic condition. The oxidation of tertiary anilines involving a single electron transfer of Fe(phen)₃(PF₆)₃ afforded the iminium ion intermediate, which reacted with electron-rich alkenes to build a six-membered N-heterocycles containing quaternary carbon center via the oxidative Povarov reaction process.

Full text of DOI:10.1002/bkcs.12273

Communication
DOI: 10.1002/bkcs.12273
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D. Y. Park et al.
KOREAN CHEMICAL SOCIETY
Fe(III)-catalyzed Oxidative Povarov Reaction With Molecular
Oxygen Oxidant
*
Du Yong Park, Joon Young Hwang, and Eun Joo Kang
Department of Applied Chemistry, Kyung Hee University, Yongin 17104, Korea.
*E-mail: ejkang24@khu.ac.kr
Received January 31, 2021, Accepted March 23, 2021
The synthesis of tetrahydroquinoline derivatives from dimethyl anilines and enamides has been developed
by Fe(III)-phenanthroline complex under aerobic condition. The oxidation of tertiary anilines involving a
single electron transfer of Fe(phen)3(PF6)3 afforded the iminium ion intermediate, which reacted with
electron-rich alkenes to build a six-membered N-heterocycles containing quaternary carbon center via the
oxidative Povarov reaction process.
Keywords: Iron(III)–phenanthroline complex, Iminium, Oxidative Povarov reaction, Oxygen,
Tetrahydroquinoline
A synthetic methodology of six-membered N-heterocycles,
which are broadly found in the natural alkaloid compounds
have been developed using various [4 + 2] cycloadditions of
conjugated heterodienes and dienophiles. The Povarov reac-
tion, known as one of the inverse-electron demand Diels–
Alder type reaction between N-aryl imine and electron-rich
alkene, generally forms a tetrahydroquinoline derivative, and
N-aryl imine is usually obtained by condensation of aniline
and aldehyde.1 As a method of preparing N-aryl imine con-
taining a stable hetero-4π systems, dehydrogenation of N-
phenyl glycine derivative or N-benzylaniline containing
electron-withdrawing or phenyl groups is performed during
the reaction process, which is named oxidative Povarov or
dehydrogenative [4 + 2] cycloaddition reaction.
On the other hand, an oxidative Povarov approach
through the N-aryl iminium intermediate instead of N-aryl
imine was explored (Scheme
1
(b)). N-Aryl
tetrahydroisoquinoline was used as a dialkylaniline sub-
strate having a structure similar to that of N-benzyl aniline
by Seidel group.7 An N-aryl iminium intermediate was
formed by single electron oxidation and hydrogen abstrac-
tion with Cu(I)Br catalyst and TBHP oxidant and then
reacted with electron-rich 1-vinylpyrrolidine-2-one to gen-
erate N-hetero polycyclic compounds. According to the
result of Huo group using Co(ClO4)2 and molecular oxy-
gen, the initially generated Co(III) peroxide radical species
abstracts the hydrogen of tertiary amine, making it an
α-aminoalkyl radical intermediate.8 Then single electron
oxidation by Co(III) species afforded iminium ions, which
reacted with dihydrofuran. Iron(III) chloride catalyst and
TBHP oxidant were also used to oxidize tertiary anilines
with forming iminium ions, and tetrahydroquinolines were
synthesized with the nucleophilic enamides.9 The oxidation
process to iminium was not clearly presented, but the reac-
tion was proved to proceed stepwise rather than a concerted
manner by DFT calculation and the experiment using a ste-
rically hindered enamide.
As discussed earlier, the activation and functionalization of
the α-amino C(sp3)-H bond to convert it to the imine and
iminium ion intermediate would be valuable due to the versa-
tile reactivity and useful compounds produced. Our strategy,
described herein, is the first iminium formation under Fe
catalysis with O2 to afford tetrahydroquinolines via addition
to electron-rich alkenes and subsequent cyclization reactions
under mild conditions, providing a sustainable redox catalysis
system. In this letter, Fe-phenanthroline complexes are shown
Various Lewis/Bronsted acid catalysis,2 transition metal
catalysis (Mn, Fe, Co, Cu, Pd)3 and photo
−/electrocatalysis4 have been reported as dehydrogenation
reactions for this purpose, and much attention have recently
been paid to iron catalysts due to the economic and oxidiz-
ing properties in first-row transition metals. The Mancheño
group carried out the oxidative Povarov reaction using
N-phenyl glycine derivative and styrene with FeCl3
(10 mol %) and TEMPO oxoammonium (2,2,6,6-
tetramethylpiperidine-1-oxonium) salt as oxidants, in which
a cycloadduct tetrahydroquinoline was obtained and further
oxidized to afford 4-phenylquinoline, N-heteroaromatic
compound (Scheme 1 (a)).5 In the reactions of N-
benzylaniline and styrene, FeCl3/DTBP and Fe(OTf)3/
acetic acid systems were developed employing excess
amount of peroxide oxidant or acid additive, and
2,4-diphenylquinolines were produced under the condi-
tion of 80 ꢀC and 140 ꢀC reaction temperature (Supporting
Information Appendix S1).6
to be a single electron oxidant of dialkylanilines, and the Fe
2+/3+
(phen)n
catalytic cycle is maintained by molecular oxy-
†These authors contributed equally to this work.
gen as the terminal oxidant.
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center 3aa was produced in 64% yield, indicating that the
Fe(III) complex selectively oxidize the aniline to iminium
enough to react with nucleophilic enamide (entry 1). The
Fe(II) complex, Fe(phen)3(PF6)2 also exhibited the reactiv-
ity in the tetrahydroquinoline formation showing a lower
yield of 46%; however, it is worthy to note that Fe(II) and
Fe(III) may be simultaneously converted in the catalytic cycle
with the aid of molecular oxygen (entry 2). Several substitu-
ents on phenanthroline ligands were applied to test the oxida-
tive reactivities of the Fe(III)-phenanthroline complexes
(entries 3–5). While 4,7-diphenyl phenanthroline (Ph2phen)
ligated complex resulted the 66% yield corresponding to the
maximum, the Fe(phen)3(PF6)3 catalyst was determined to be
the optimal Fe(III) complex to effect this oxidative Povarov
cyclization in experiments with increased amount (7 mol %)
of catalysts (entries 6–7). Iron(III) and iron(II) salts such as
FeCl3, FeCl2, FeBr2, and Fe(acac)3 did not afford any cyclo-
addition product as well as addition product (entry 8). Exami-
nation of the reaction medium resulted that aprotic polar
solvent, dimethyl sulfoxide (DMSO) was optimal for this oxi-
dative cyclization, and decreasing the amount of
dimethylaniline (1a) achieved only 43% yield (entries 9–13).
Experiments in the absence of the Fe catalyst failed to proceed
any oxidative initial step (entry 16).
Scheme 1. Oxidative Povarov reactions for six-membered
N-heterocycles .
In our previous report on the use of iron–phenanthroline
complex, iron catalyst exhibited well-matched oxidation
potential to oxidize amines as well as alkenes without high-
energy irradiation, and generated α-aminoalkyl radical spe-
cies were reacted with electrophilic maleimides in [4 + 2]
cycloaddition reactions.10 Therefore, we initially focused
our studies on the oxidative Povarov cyclization reactions
of N,N-dimethylaniline (1a) and N-(1-phenylvinyl)acet-
amide (2a) using a simple iron complex Fe(phen)3(PF6)3
under DMSO and air condition (Table 1). To our delight,
the desired tetrahydroquinoline with quaternary carbon
With the best conditions for tetrahydroquinoline synthe-
sis, the generality of this oxidative Fe catalysis was investi-
gated regarding the aniline and enamide scope (Table 2).
Table 1. Oxidative Povarov reaction conditions.a
Entry
Fe complex (x mol %)
Solvent
Temp. (ꢀC)
Yield (%)
1
2
3b
4b
5b
6
7
8
9
10
11
12
13c
14
15
16
Fe(phen)3(PF6)3 (5)
Fe(phen)3(PF6)2 (5)
Fe(Me2phen)3(PF6)3 (5)
Fe(Me4phen)3(PF6)3 (5)
Fe(Ph2phen)3(PF6)3 (5)
Fe(Ph2phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
FeCl3 (5)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
Fe(phen)3(PF6)3 (7)
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
DMF
CH3CN
DCE
DMSO
DMSO
DMSO
DMSO
50
50
50
50
50
50
50
50
50
50
50
50
50
70
rt
64
46
52
64
66
68
72
-
69
42
55
41
43
38
64
-
50
a Reaction conditions: 1a (1.0 mmol), 2a (0.2 mmol), Fe complex (x mol %), solvent (2 mL), isolated yields.
b Ph2phen = 4,6-diphenyl-1,10-phenanthroline, Me2phen = 2,9-dimethyl-1,10-phenanthroline, Me4phen = 3,4,7,8-tetramethyl-1,10-phenanthroline.
c Reaction with 1a (0.6 mmol).
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Table 2. Substrate scope of tetrahydroquinoline synthesis.
Scheme 2. Mechanistic investigation.
Figure 1. Proposed mechanism.
dimethylanilines were more challenging, therefore anilines
having two different N-alkyl groups such as benzyl/methyl
(3ja) and ethyl/methyl (3ia), aminomethyl radicals were
exclusively generated and C C bond formation took place
on the N-methyl carbon in low yield (12–23%).
From the above results, it can be concluded that the [4
+ 2]-type cycloaddition occurs between the electrophilic
heterodiene, that is, N-aryl iminium intermediate and
electron-rich enamide. Although the reaction of
dialkylaniline under the similar catalytic conditions of
Fe(phen)3(PF6)3 under aerobic oxidation, it differs from the
radical mechanism of the previous study that carried out
radical addition and cyclization reaction with electron-
deficient maleimide. Several mechanistic experiments were
performed in order to reveal the mechanism of this transfor-
mation (Scheme 2). Notably, the reaction of N,N-
dimethylaniline (1a) and dihydrofuran resulted the
tetrahydrofuroquinoline 5, which supports the reaction roles
of dihydrofuran as nucleophile as the previous reports on
Co(II)-catalyzed aerobic oxidation by Huo. A well-known
nucleophile nitromethane transformed to the addition prod-
uct 7 in 46% yield. Additionally, a radical trapping reagent,
TEMPO, markedly suppressed the reaction (Scheme 2, Eq.
(3)), suggesting that radical species are involved during the
Fe(III) and molecular oxygen system.10b
With electro-donating alkyl substituents on the aryl group
in enamide, the corresponding tetrahydroquinolines (3ab
and 3ac) were accessed in good yield, and trifluoromethyl,
fluoro and chloro substituents were also amenable in this
Fe-catalyzed cyclization (3ad–3ag). Pyridine hetero-
aromatic group was well tolerated to afford the desired
product (3ah). Various N,N-dimethylanilines incorporating
4-OMe and 4-X delivered a range of tetrahydroquinolines
in moderate to good yield (3ba–3fa). The EWG substitu-
ents of the aniline could be expected to destabilize the first
N-aryl iminium intermediate and decrease the nucleophilic-
ity of the aryl group in the electrophilic aromatic
substitution step, resulting the lower yield. N,N-
Dimethylnaphthalen-1-amine (1h) also participated in
oxidative Povarov Fe catalysis and produced polycyclic
hetero compound, 3ha in 34% yield. Substrates other than
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The mechanism of oxidative Mannich reaction with tert-
butyl hydroperoxide, which is the basis of the oxidative
Povarov cyclization, was investigated and reported by the
Doyle group, in terms of roles of transition metal salt.11 It
was concluded that the general role of Cu(I), Fe(III),
Co(II), and Ru(II) salts is to initiate the conversion of
TBHP to tert-butylperoxy radicals, which is the thermody-
namically preferred oxidant in the rate-determining single
electron transfer (SET) step. Therefore, a proposed mecha-
nism for the Fe(phen)3(PF6)3 and oxygen system in the
absence of peroxide oxidant, described herein, might be
drawn in Figure 1. The first SET step is proposed to be
proceeded between Fe(III) complex and the dimethylaniline
(1a) to produce an amine radical cation intermediate I and
Fe(II) complex, which is accountable with the potentials of
the Fe(III)/Fe(II) (1.10 V vs. SCE) and amine/radical cation
redox pairs (0.78 V vs. SCE).12 Deprotonation and subse-
quent oxidation yield the iminium ion III, which adds to
enamide (2a) producing the Mannich-type addition intermedi-
ate IV. Electrophilic arylation and deprotonation furnish the
desired tetrahydroquinoline product 3aa. Critically, the
Fe(II) complex produced in the first SET step is found to be
oxidized forming the Fe(III) OO (peroxo) or Fe(III) OOH
complexes with O2. The HOO¯ ligand could be dissociated
and involved with deprotonation step, and Fe(phen)33+ would
be regenerated for the oxidative catalytic cycle.
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tetrahydroquinoline product. Mechanistically, the Fe(II)–Fe
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Acknowledgments. This study was supported by the GRRC
program of Gyeonggi province [GRRC-kyunghee2017
(A01, B02)].
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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