Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines through Formal [4+2] Cycloaddition of Acyclic α,β-Unsaturated Amides and Imides with N,N-Dialkylanilines

Article abstract of DOI:10.1002/chem.202004186

1,2,3,4-Tetrahydroquinolines should be applicable to the development of new pharmaceutical agents. A facile synthesis of 1,2,3,4-tetrahydroquinolines that is achieved by a photoinduced formal [4+2] cycloaddition reaction of acyclic α,β-unsaturated amides and imides with N,N-dialkylanilines under visible-light irradiation, in which a new Ir^III complex photosensitizer, a thiourea, and an oxidant act cooperatively in promoting the reaction, is reported. The photoreaction enables the synthesis of a wide variety of 1,2,3,4-tetrahydroquinolines, while controlling the trans/cis diastereoselectivity (>99:1) and constructing contiguous stereogenic centers. A chemoselective cleavage of an acyclic imide auxiliary is demonstrated.

Full text of DOI:10.1002/chem.202004186

Accepted Article
Accepted Article
Title: Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines
via Formal [4+2] Cycloaddition of Acyclic α,β-Unsaturated Amides
and Imides with N,N-Dialkylanilines
Authors: Kennosuke Itoh, Shun-ichi Nagao, Ken Tokunaga, Shigeto
Hirayama, Fumika Karaki, Takaaki Mizuguchi, Kenichiro
Nagai, Noriko Sato, Mitsuaki Suzuki, Masashi Hashimoto, and
Hideaki Fujii
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202004186
Link to VoR: https://doi.org/10.1002/chem.202004186
01/2020

10.1002/chem.202004186
Chemistry - A European Journal
RESEARCH ARTICLE
Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines
via Formal [4+2] Cycloaddition of Acyclic α,β-Unsaturated Amides
and Imides with N,N-Dialkylanilines
Kennosuke Itoh*, Shun-ichi Nagao, Ken Tokunaga, Shigeto Hirayama, Fumika Karaki, Takaaki
Mizuguchi, Kenichiro Nagai, Noriko Sato, Mitsuaki Suzuki, Masashi Hashimoto and Hideaki Fujii*
Abstract: 1,2,3,4-Tetrahydroquinolines should be applicable to the
development of novel pharmaceutical agents. We report a facile
synthesis of 1,2,3,4-tetrahydroquinolines that was achieved by a
photo-induced formal [4+2] cycloaddition reaction of acyclic α,β-
unsaturated amides and imides with N,N-dialkylanilines under visible-
light irradiation where a novel Ir(III) complex photo-sensitizer, a
thiourea, and an oxidant act cooperatively in promoting the reaction.
The photo-reaction enables the synthesis of a wide variety of 1,2,3,4-
tetrahydroquinolines while controlling trans/cis diastereoselectivity
reactions,[8] secondary amine-catalyzed reactions,[9] bifunctional
amine-thiourea-catalyzed reactions,[10] iodonium ion-promoted
reactions,[11] cyclopropane ring-opening reactions,[12] o-
azaxylylene-mediated reactions,[13] intramolecular cyclization
reactions of nitrogen-nucleophiles to indoles and oxindoles,[14]
and transformation reactions of quinolines.[15,16] Besides, three
types of straightforward photochemical reactions afford the
syntheses of 1,2,3,4-THQs. Among them, photochemically
[17]
promoted aza-Diels-Alder type reactions
and the photo-
(>99:1) and constructing contiguous stereogenic centers.
A
induced aerobic decarboxylative Povarov reaction[18] have been
chemoselective cleavage of an acyclic imide auxiliary is demonstrated. developed in recent years. Photo-induced formal [4+2]
cycloaddition reactions of α,β-unsaturated carbonyl compounds
with N,N-dialkylanilines have long been studied, but the most
commonly reported reactions involved the use of maleimides as
Introduction
a reaction partner of N,N-dialkylanilines.[19] Hence, it has been
difficult to introduce different types of substituents in the resulting
1,2,3,4-THQs and to produce the cis-stereoisomer. A few
examples of the reaction using cyclic α,β-unsaturated ketones,
cyclic lactones, and cyclic amides instead of maleimides have
been reported, however, the reactions are limited in terms of poor
substrate generality and low yield of 1,2,3,4-THQs.[20]
1,2,3,4-Tetrahydroquinoline (1,2,3,4-THQ) is a promising
scaffold for drug discovery.[1]
A number of 1,2,3,4-THQs
possessing an affinity for biological systems have been
developed in medicinal chemistry.[2] We were able to discover a
1,2,3,4-THQ framework in the structure of naturally occurring
molecules which showed a wide variety of biological activities.[3]
Because of the significance with biological relevance of 1,2,3,4-
THQs, a number of non-photochemical reactions for construction
of a 1,2,3,4-THQ skelton[4] have been developed such as formal
[4+2] cycloaddition reactions of maleimides and a very few acyclic
α,β-unsaturated compounds with N,N-dialkylanilines,[5] Povarov
reaction,[6] metal-mediated reactions,[7] Brønsted acid-catalyzed
The reaction of acyclic α,β-unsaturated compounds with N,N-
dialkylanilines has the possibility of enabling syntheses of 1,2,3,4-
THQs possessing a wide variety of substituents with control of
trans/cis diastereoselectivity and enantioselectivity. However,
there are very few reports of the photo-induced and the non-
photo-induced reactions using acyclic α,β-unsaturated
compounds,
e.g.,
arylidene
malononitrile,[21]
dialkyl
fumarate,[5b,7d,20d] and 1-(2-alkenoyl)-3,5-dimethylpyrazole.[22]
Among the three types of acyclic α,β-unsaturated compounds, 1-
(2-alkenoyl)-3,5-dimethylpyrazole has utilized for the reaction of
[*]
Prof. Dr. K Itoh, S. Nagao, Dr. S. Hirayama, Dr. F. Karaki, Dr. T.
Mizuguchi, Prof. Dr. Hideaki Fujii
N,N-dialkylaniline to give 1,2,3,4-THQs where
chelation complex of chiral Lewis acid, (R,R)-DBFOX/Ph•Ni(II)[23]
with 1-(2-alkenoyl)-3,5-dimethylpyrazole serves as
photocatalyst,[22] however, only two reactions have been
demonstrated. As a result, trans/cis diastereoselectivities are high
without revealing relative configurations, however, enantiomeric
excesses are almost zero.
In Scheme 1, we depict a proposed mechanism for the photo-
induced formal [4+2] cycloaddition reaction of α,β-unsaturated
compounds with N,N-dialkylanilines I.[24] The photo-sensitizer
(Sens.) absorbs light to generate the excited state photo-
sensitizer (*Sens.) which is subsequently quenched by N,N-
dialkylaniline I via single electron transfer (SET) to give the amine
a bidentate
Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato
University, Tokyo 108-8641 (Japan)
E-mail: itok@pharm.kitasato-u.ac.jp
Prof. Dr. K Itoh, Dr. S. Hirayama, Dr. F. Karaki, Dr. T. Mizuguchi, Dr.
Kenichiro Nagai, Noriko Sato, Prof. Dr. Hideaki Fujii
Medicinal Research Laboratories, School of Pharmacy, Kitasato
University, Tokyo 108-8641 (Japan)
Dr. M. Suzuki, Prof. Dr. M. Hashimoto
Department of Chemistry, Faculty of Science, Josai University,
Saitama 350-0295 (Japan)
Prof. Dr. Ken Tokunaga
Division of Liberal Arts, Center for Promotion of Higher Education,
Kogakuin University, Tokyo 192-0015 (Japan)
a
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202004186
Chemistry - A European Journal
RESEARCH ARTICLE
Scheme 1. An overview of the photo-induced formal [4+2] cycloaddition of cyclic
α,β-unsaturated compounds with N,N-dialkylanilines.
radical cation II and the reduced photo-sensitizer (Sens.•−). The
amine radical cation II induces proton transfer (PT) to provide the
α-aminoalkyl radical III. The resulting α-aminoalkyl radical III
reacts with the radical acceptor through radical conjugate addition
(RCA) to afford the α-carbonyl radical IV which follows two
different fates. One is formation of the conjugate adduct V along
with the re-generated Sens. where the α-carbonyl radical IV is
subject to SET by reaction of Sens.•− to give the corresponding
enolate which subsequently reacts with the amine radical cation
II via PT. The other pathway forms the desired 1,2,3,4-THQ along
with the reduced product VIII. The α-carbonyl radical IV
undergoes radical cyclization to generate the cyclohexadiene π-
radical VI which subsequently reacts with the radical acceptor via
SET followed by PT or N,N-dialkylanilines I via hydrogen atom
transfer (HAT). Eventually, the cyclohexadiene π-radical VI
completes aromatization to give 1,2,3,4-THQ. The sequential
radical cyclization-aromatization is termed homolytic aromatic
substitution (HAS).[25,26] To complete HAS, the cyclohexadiene π-
radical VI must be oxidized by the radical acceptor or an oxidizing
additive[20a,20b] to form 1,2,3,4-THQ along with α-carbonyl radical
VII via SET followed by PT. The α-carbonyl radical VII reacts with
Sens.•− and a proton to give the reduced product VIII and
Sens.[19b,19e,19g] There is a possibility that the α-carbonyl radical VII
abstracts hydrogen of N,N-dialkylanilines I to afford the reduced
product VIII and α-aminoalkyl radical III.[20b,20f,20g] Formation of the
reduced product VIII is inevitable and sacrifices the yield of
1,2,3,4-THQ.[20g] Intrinsically, LUMO and SOMO energy levels of
maleimides and the corresponding α-carbonyl radical IV are close
to the SOMO and HOMO energy levels of the α-aminoalkyl radical
III and aromatic ring, respectively. Additionally, an excess amount
of maleimides is necessary to obtain 1,2,3,4-THQs unless
molecular oxygen is used as an oxidizer.[15] Therefore,
maleimides are allowed to be utilized as a radical acceptor without
critical problems.
We envisioned that
a
photo-induced formal [4+2]
cycloaddition of acyclic α,β-unsaturated compounds with N,N-
dialkylanilines would be developed by carrying out the following
points: (i) Using a novel Ir(III) complex photo-sensitizer (Ir(III)
complex)[27], a facile formation of the α-aminoalkyl radical III and
a disturbing formation of the conjugate adduct V would be
achieved by an excellent oxidizing ability of an excited Ir(III)
complex (corresponding to *Sens.) and a suitable reactivity of a
Ir(II) complex (corresponding to Sens.•−); (ii) Using thioureas,
LUMO and SOMO energy levels of the acyclic α,β-unsaturated
carbonyl compound and the α-carbonyl radical IV would be
controlled by a hydrogen-bonding interaction to make reaction
pathways converge with formation of the cyclohexadiene π-
radical VI with control of trans/cis diastereoselectivity and
enantioselectivity; (iii) Using azo compounds,
a
facile
aromatization of the cyclohexadiene π-radical VI would be
accomplished and precluded formation of the reduced product
VIII by oxidation.
Herein, we present the first photo-induced formal [4+2]
cycloaddition reaction of a wide variety of acyclic α,β-unsaturated
compounds with N,N-dialkylanilines to give 1,2,3,4-THQs in a
highly diastereoselective manner. The cooperative action of a
novel Ir(III) complex, a thiourea, and an azo compound is the key
to the success of this reaction.
Results and Discussion
We chose 1-crotonoyl-3,5-dimethylpyrazole (1a) as the
acyclic α,β-unsaturated carbonyl compound, because 1a was
known as a good radical accepter (Table 1).[22,28] The reaction of
1-crotonoyl-3,5-dimethylpyrazole (1a) with N,N-dimethylaniline
(2) did not occur in the absence of an Ir(III) complex under visible-
light-irradiation (entry 1). The first attempt to use Ir(III) complex 4a,
however, afforded a slight amount of 1,2,3,4-THQ 5aa with a poor
ratio of 1,2,3,4-THQ 5aa to conjugate adduct 6 and high
diastereomeric ratio (d.r.) (entry 2). We could not detect the
reduced product, 1-butanoyl-3,5-dimethylpyrazole (7), because a
number of by-products interrupted spectroscopic identification for
formation of 7 even after attempting chromatographic isolation.
Based on these results, we decided to add thiourea 3a as a
Brønsted acid,[29] because 3a has been recognized as a good
hydrogen-bonding donor in the amine conjugate addition to
facilitate the reaction rate by controlling LUMO energy levels of 1-
(2-alkenoyl)-3,5-dimethylpyrazole (1a).[30] In our photochemical
reaction, the use of thiourea 3a made a significant impact not only
by enhancing the reaction rate, but also favoring formation of
1,2,3,4-THQ 5aa (entry 3). Since the reaction of 1-crotonoyl-3,5-
dimethylpyrazole (1a) with N,N-dimethylaniline (2) occurred in the
presence of thiourea 3a and Ir(III) complex 4a, we screened Ir(III)
complexes. No reaction was induced when tris(2-
phenylpyridine)iridium(III) (4b) was used (entry 4). Iridium(III)
complex 4c, having electron-withdrawing methoxycarbonyl
groups in the bipyridine ligand, could not promote the reaction
(entry 5). Using iridium(III) complex 4d with the electron-donating
O
X
Y
O
X
Y
O
R2
R2
R1
n
n
R1
R1
+
X
N
R2
R2
N
N
Y
n
R2
R2
Radical
acceptor
α-Aminoalkyl radical
Cyclohexadiene π-radical
α-Carbonyl radical
III
VI
IV
Radical
acceptor
O
SET
PT
H+
PT
X
R2
Y
R1
n
N
α-Carbonyl radical
VII
R2
Amine radical cation
II
Sens.
SET
PT
or HAT
H+
or
I
Sens.
Sens.
or
II
SET
PT
SET
O
X
*Sens.
Sens.
Y
n
hν
Reduced product
VIII
R2
X
Y
n
O
X
Y
O
R1
N
n
R1
R1
R2
R2
R2
N
N
N,N-Dialkylaniline
I
R2
R2
Conjugate adduct
1,2,3,4-THQ
V
Desired product
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10.1002/chem.202004186
Chemistry - A European Journal
RESEARCH ARTICLE
tert-butyl group in the bipyridine ligand gave results comparable
with entry 3 (entry 6). Using Ir(III) complex 4e, possessing a
different counter anion from Ir(III) complex 4d, slightly decreased
the yield and d.r. of 1,2,3,4-THQ 5aa (entry 7). In the presence of
Ir(III) complex 4f possessing an electron-donating methoxy group,
the reaction occurred cleanly and led to identification of 1,2,3,4-
THQ 5aa, conjugate adduct 6, and the reduced product 7 (entry
8). We designed and synthesized a novel Ir(III) complex 4g having
fluoro and trifluoromethyl groups in the phenyl pyridine ligand
(entry 9). The introduction of the fluorine group into phenyl
pyridine ligand was predicted to diminish the radiative rate
constant and spin-orbit coupling strength, resulting in an
extension in triplet lifetime of Ir(III) complex 4g, which would
increase the efficiency of SET from N,N-dimethylaniline (2) to the
photo-excited 4g.[31] Consequently, formation of the reduced
product 7 was not observed, and besides, the yield of 1,2,3,4-
THQ 5aa and diastereomeric ratio were the best by using Ir(III)
complex 4g.
1
2
3
4
5
6
7
8
9
none
4a
none
none
yes
43
111
46
24
37
23
17
23
23
0
–
9 (67:33)
31 (91:9)
0
97:3
96:4
–
4a
4b
4c
yes
yes
0
–
4d
4e
yes
38 (95:5)
29 (91:9)
38 (94:6)[d]
38 (96:4)
93:7
92:8
94:6
96:4
yes
4f
yes
4g
yes
[a] Yield of 5aa. [b] Ratio of 5a and 6 in the crude mixture was
determined by 1H NMR. [c] Determined by 1H NMR of the crude
mixture. [d] 7 was isolated in 50% yield.
Solvents affected the reaction efficiency and the product ratio
of 1,2,3,4-THQ 5aa to conjugate adduct 6 (see Supporting
Information (SI)). The reaction did not occur in aerated solutions,
suggesting that the reaction proceeded through the triplet excited
state of reagents.
The relative configurations of the major isomer and the minor
isomer of 1,2,3,4-THQ 5aa were determined by X-ray
crystallographic analyses[32] and NMR analyses to reveal 3,4-
trans and 3,4-cis, respectively. Therefore, the radical conjugate
addition (RCA) followed by homolytic aromatic substitution (HAS)
occurred in a syn-selective manner to give the 3,4-trans isomer
predominantly. Enantiomeric excesses of 1,2,3,4-THQ 5aa in
Table 1 were almost zero. The structure of the novel Ir(III)
complex 4g was confirmed by X-ray crystallographic analyses[32]
and NMR analyses (Figure 1 and SI).
Figure 1. ORTEP drawing of Ir(III) complex 4g: All disordered carbon atoms, a
solvent, and an oxygen of crystal water were omitted for clarify.
We next added an azo compound to prevent the production of
the reduced product 7 and to concomitantly promote the oxidation
Table 1: 1-Crotonoyl-3,5-dimethylpyrazole as a radical acceptor in the
presence of Ir (III) complex photo-sensitizers and a thiourea.
of
the
cyclohexadiene
π-radical,
because
2,2'-
CF3
azobis(isobutyronitrile) (AIBN) is known to be a good oxidizing
agent for the cyclohexadiene π-radical (Table 2).[24-26] Iridium(III)
complex 4f was used for the evaluation of azo compounds,
because 4f could be prepared much easier than Ir(III) complex 4g.
Contrary to expectations, AIBN did not work well in our reaction
(entry 1). After the investigation with other azo compounds such
as V-601, V-65, and V-70 (entries 2−4), we found that V-70 was
the optimal oxidant (entry 4). Reducing the amount of V-70 by half
(200 mM), the yield of 1,2,3,4-THQ 5aa was decreased to 40%
without affecting the product ratio of 5aa to conjugate adduct 6
and d.r. of 5aa. Finally, we observed that the combined use of V-
70 and Ir(III) complex 4g gave the best result (entry 5). Various
types of oxidants, e.g., acetone,[20b] 1,4-benzoquinone, methyl
viologen, electron-deficient alkenes, and potassium persulfate did
not play a role (see SI). We confirmed that the reaction did not
occur in the absence of Ir(III) complex; a gas was evolved without
forming 1,2,3,4-THQ 5aa (entry 6). The gas would be nitrogen gas
evolved by decomposition of V-70 to generate a carbon radical.
Hence, we concluded that V-70 could not act as a radical initiator
in the reaction. The diastereomeric ratio of 1,2,3,4-THQ 5aa was
S
F3C
N
N
H
H
O
H3C
CH3
OH
Thiourea 3a (100 mM)
Photo-sens. 4a−4g (5 mM)
white LED (λ = 400−780 nm)
N
N
H3C
N
CH3
+
CF3C6H5 (deaerated), rt
CH3
1a
(100 mM)
2a
(1 M)
H3C
CH3
N
CH3
O
N
N
O
Ph
O
N
N
CH3
H3C
H3C
N
CH3
N
CH3
+
+
N
CH3
CH3
CH3
5aa
ORTEP drawing of 5aa
6
7
Photo-sens.
X
R2
R3
R1
N
Ir
4a: R1= R2= R3= R4= H, X= −BF4
R4
N
Ir
4c: R1= R2= R4= H, R3= CO2CH3, X= −BF4
4d: R1= R2= R3= H, R4= t-Bu, X= −PF6
4e: R1= R2= R3= H, R4= t-Bu, X= −BF4
4f: R1= R2= R3= H, R4= CH3O, X= −BF4
4g: R1= F, R2= CF3, R3= H, R4= CH3O, X= −BF4
N
R1
R1
N
N
N
R4
N
R3
R1
4b
R2
4a, 4c−4g
entry
photo-
sens.
3a
time
[h]
yield [%]
(5aa:6)[a],[b]
d.r. of 5aa
(trans:cis)[c]
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10.1002/chem.202004186
Chemistry - A European Journal
RESEARCH ARTICLE
comparable whether V-70 was added or not. Enantiomeric
excesses of 1,2,3,4-THQ 5aa in Table 2 were almost zero.
thiourea 3a (100 mM)
photo-sens. 4g (5 mM)
V-70 (400 mM)
O
Aux
CH3
H3C
CH3
N
O
white LED (λ = 400−780 nm)
+
Aux
CH3
CF3C6H5 (deaerated), rt
N
Table 2: Evaluation of azo compounds.
CH3
5ba, 5ca,
5da, 5ea
1b−1e
(100 mM)
2a
(1 M)
thiourea 3a (100 mM)
photo-sens. 4f or 4g (5 mM)
oxidant (400 mM)
O
H3C
CH3
Aux:
O
N
O
N
N
H3C
N
CH3
H3C
H3C
white LED (λ = 400−780 nm)
N
H
+
O
CF3C6H5 (deaerated), rt
CH3
CH3
1c
1a
(100 mM)
2a
(1 M)
H3C
1b
CH3
N
O
CH3
O
O
N
N
O
Ph
N
H
N
N
CH3
H3C
N
CH3
H
+
OCH3
1e
ORTEP drawing of 5da
N
CH3
1d
(Aux = C6H5)
CH3
5aa
6
photo-sens.:
R1
Oxidant:
CH3
CN
CH3
CO2CH3
−BF4
entry
alkene
1b
d.r. (trans:cis)[b]
time [h]
70
yield [%][a]
R2
H3C
NC
N
N
H3C
H3CO2C
N
CH3
N
CH3
OCH3
CH3
AIBN
CH3
V-601
CH3
H3CO CH3
N
Ir
1
2
3
4
35 (5ba)
22 (5ca)
60 (5da)
60 (5ea)
>99:1
>99:1
N
N
R1
R1
H3C
CH3
N
CH3
CN
CH3
CN
OCH3
1c
70
N
N
R1
N
N
R2
NC
NC
1d
43
>99:1
CH3
CH3
H3C
CH3
H3C
OCH3
CH3
4f: R1= R2= H
4g: R1= F, R2= CF3
V-65
V-70
1e
43
>99:1[c]
entry
photo-
sens.
oxidant
time [h]
d.r. of 5aa
(trans:cis)[c]
yield [%]
(5aa:6)[a],[b]
[a] Isolated yield. [b] Determined by 1H NMR of the crude mixture. [c]
Ee of 5ea was 12%.
1
2
3
4
5
6
4f
4f
AIBN
V-601
V-65
V-70
V-70
V-70
70
23
47
46
70
23
21 (98:2)
33 (97:3)
39 (96:4)
56 (97:3)
64 (94:6)
0
98:2
98:2
97:3
98:2
94:6
–
Next, we synthesized several chiral thioureas to exert
enhanced enantioselectivity (Table 4).[37] Thiourea 3b, having the
((S)-2-amino-(1,10-binaphthalen)-2-ol) (NOBIN)[37] scaffold, was
not effective for promoting the reaction (entry 1). The reaction in
the presence of chiral thiourea 3c having a (S)-1,1'-binaphthyl-
2,2'-diamine (BINAM) backbone afforded 1,2,3,4-THQ 5ea in
good yield with 15% ee (entry 2). We synthesized a novel thiourea
3d possessing phenyl groups on the 3,3'-positions of BINAM
backbone which was expected to shield one enantioface of α,β-
unsaturated imide 1e (entry 3). Contrary to expectations, the
reaction was decelerated and ee was decreased. Adding chiral
urea 3e[38] was not effective in proceeding with the reaction
because of the poor solubility of 3e (entry 4). Using thiourea 3f
having 5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl-2,2'-diamine
(H8-BINAM), the reaction rate was decreased, but ee was the
same as entry 2 (entry 5). Other chiral thioureas and achiral
4f
4f
4g
none
[a] Yield of 5aa. [b] Ratio of 5a and 6 in the crude mixture was
determined by 1H NMR. [c] Determined by 1H NMR of the crude
mixture.
With the optimal reaction conditions in hand, we evaluated
several acyclic α,β-unsaturated compounds including different
auxiliaries, e.g., 2-oxazolidinone 1b,[33] tert-butyl amide 1c,[34]
benzamide 1d,[35] and 2-methoxybenzamide 1e[36] (Table 3). All
reactions progressed in the exclusive formation of 1,2,3,4-THQs
5ba–5ea with excellent diastereoselectivities. The yields of
1,2,3,4-THQs 5ba and 5ca were low (entries 1 and 2), however,
those of 1,2,3,4-THQs 5da and 5ea were moderate (entries 3 and
4). Enantiomeric excesses of 1,2,3,4-THQs 5ba–5ea were low.
Among them, 1,2,3,4-THQs 5ea was obtained in moderate yield
with 12% ee (entry 4). Finally, we clarified α,β-unsaturated imide
1e as the suitable radical acceptor. We succeeded in X-ray
crystallographic analysis of 1,2,3,4-THQ 5da which was the 3,4-
trans isomer.[32]
thiourea,
i.e.,
1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea[39]
possessing high acidity of the NH proton were not effective (see
SI). Finally, chiral thiourea 3c derived from BINAM induced the
best ee, even though the outcome still had plenty of room for
improvement. Hence, we concluded that a highly enantioselective
reaction could be achieved by reducing the rotatability of carbon-
nitrogen bonds of chiral thioureas. Consequently, we directed
toward establishing the formal [4+2] cycloaddition reaction under
achiral reaction conditions. We also assessed the reaction of a
cyclic α,β-unsaturated carbonyl compound, N-phenylmaleimide
with N,N-dimethyl-4-methylaniline (2b) to give the corresponding
1,2,3,4-THQ in 72% yield even in the absence of thiourea (see SI).
Hence, we were truly convinced that the thiourea was
indispensable to promote the reaction of acyclic α,β-unsaturated
amides and imides.
Table 3: Evaluation of auxiliaries.
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10.1002/chem.202004186
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RESEARCH ARTICLE
groups of 4-fluoro-N,N-dimethylaniline 2e and 4-bromo-N,N-
dimethylaniline 2f slightly improved the yields of 1,2,3,4-THQs
5ee and 5ef along with decreasing the rates of the reactions.
According to detailed kinetic studies, acidity of the N-methyl
proton of amine radical cations is a very important factor toward
facile formation of α-aminoalkyl radicals.[41] Hence, electron-
withdrawing 4-fluoro and 4-bromo groups would increase acidity
of the N-methyl proton of amine radical cations, enabling the facile
formation of α-aminoalkyl radicals. Consequently, increasing the
lability of the N-methyl proton would contribute to acceleration of
the radical conjugate addition reaction, thereby increasing the
yield of 1,2,3,4-THQs 5ee and 5ef. In contrast, electron-
withdrawing 4-fluoro and 4-bromo groups would decelerate
radical cyclization, because the HOMO-SOMO energy gap
between their aromatic rings and the corresponding α-carbonyl
radical intermediates would become larger. The reaction of α,β-
unsaturated imides 1e with N,N-dimethyl-3-methylaniline (2g)
occurred in a regioselective manner at the para-position of the
aromatic methyl group to give 1,2,3,4-THQ 5eg exclusively
because the aromatic methyl group served as the steric bulk in
the radical cyclization step (Table 5(iii)). The reaction of N,N-
dimethyl-3-fluoroaniline (2h) with α,β-unsaturated imide 1e gave
a mixture of 7-fluoro and 5-fluoro-1,2,3,4-THQs 5eh in the ratio of
70:30. This result suggested that the fluoro group was sterically
less demanding than the methyl group. Thus, radical cyclization
would occur with low regioselectivity (See SI).
Table 4: Evaluation of chiral thiourea derivatives.
thiourea 3b−3e (100 mM)
O
Aux
CH3
photo-sens. 4g (5 mM)
V-70 (400 mM)
white LED (λ = 400−780 nm)
H3C
CH3
N
O
+
Aux
CH3
CF3C6H5 (deaerated), rt
N
O
Aux:
1e
(100 mM)
2a
(1 M)
CH3
N
5ea
d.r. >99:1
H
OCH3
Thiourea:
CF3
CF3
CF3
R
S
X
S
S
N
N
H
CF3
N
N
H
H
N
CF3
CF3
N
H
H
N
N
H
H
N
CF3
CF3
H
H
H
N
OH
3b
X
R
CF3
CF3
3c: X = S, R = H, 3d: X = S, R = Ph
3e: X = O, R = H
3f
time [h]
48
yield [%][a]
ee [%][b]
entry
thiourea
3b
1
2
3
4
5
3]
65
7
3c
48
15
10
–
3d
48
24
3e
48
trace
20
3f
48
15
[a] Isolated yield. [b] Determined by chiral HPLC.
Table 5: Exploring of substrate scope.[a]
thiourea rac-3c (100 mM)
photo-sens. 4g (5 mM)
V-70 (400 mM)
O
Aux
R1
We decided to use racemic thiourea 3c (rac-3c) for exploring
the substrate scope (Table 5). We evaluated substituents at the
β-position of α,β-unsaturated imides 1e–1k (Table 5(i)). The
reaction using thiourea rac-3c demonstrated comparable results
with a chiral version depicted in entry 2, Table 4. The yields of
1,2,3,4-THQs 5ea–5ha possessing different functional groups
such as methyl, isobutyl, trifluoromethyl, and phenyl groups were
comparable with each other. The rate of reaction was affected by
size, electron-donating and electron-withdrawing abilities of
substituents at the β-position of α,β-unsaturated imides. The p-
fluoro group of the benzene ring at the β-position of α,β-
unsaturated imide 1i would increase electrophilicity, which
appeared to accelerate the conjugate addition step. However,
formation of by-products of unknown structure compromised the
yield of 1,2,3,4-THQ 5ia, which might be due to radical ipso-
substitution of the carbon-fluorine bond.[40] Alternatively, an
electron-donating p-methoxy and 3-furyl group would reduce
electrophilicity of α,β-unsaturated imides 1j and 1k and caused
formation of a number of by-products to decrease the yield of
1,2,3,4-THQs 5ja and 5kb. Several N,N-dimethylanilines 2b–2f
having electron-donating and electron-withdrawing substituents
at the para-position on the benzene ring were evaluated (Table
5(ii)). N,N-Dimethyl-4-methylaniline (2b) was a particularly good
substrate which reacted with α,β-unsaturated imides 1e and 1g to
give 1,2,3,4-THQs 5ea and 5gb in good to excellent yields. Other
N,N-dimethylanilines possessing electron-donating substituents
such as benzyl and methoxy groups prolonged the reaction times
and reduced the yields of 1,2,3,4-THQs 5ec, 5ed, and 5gd.
Electron-withdrawing substituents such as fluoro and bromo
H3C
CH3
O
N
white LED (λ = 400−780 nm)
R1
R2
Aux
+
R2
CF3C6H5 (deaerated), rt
N
1e−1k
(100 mM)
O
Aux:
CH3
2a−2h
(1 M)
5ea−5eh
d.r. >99:1
N
H
OCH3
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10.1002/chem.202004186
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RESEARCH ARTICLE
(i) Evaluation of substituents at the β-position of (E)-N-(2-alkenoyl)-2-methoxybenzamide
HO
+
(a)
thiourea rac-3c (100 mM)
photo-sens. 4g (5 mM)
CH3
V-70 (400 mM)
O
Aux
O
Aux
O
Aux
O
Aux
O
Aux
CH3
CH3
CH3
CH3
CF3
N
white LED (λ = 400−780 nm)
N
N
N
N
1e
(100 mM)
CF3C6H5 (deaerated), rt, 96 h
CH3
5ea
48 h, 62%
CH3
5fa
126 h, 61%
CH3
5ga
25 h, 61%
CH3
5ha
25 h, 53%
N
O
Aux:
OH
2i
(1 M)
N
5ei
O
Aux
F
O
Aux
OMe
H3C
O
Aux
H
OCH3
29%, d.r. >99:1
O
N
N
N
thiourea rac-3c (100 mM)
photo-sens. 4g (5 mM)
V-70 (400 mM)
(b)
O
Aux
CF3
CH3
CH3
5ia
25 h, 30%
CH3
5ja
25 h, 29%
CH3
5kb
48 h, 41%
H3C
N
CH3
H3C
white LED (λ = 400−780 nm)
1g
+
(ii) Evaluation of substituents on the para-position of N,N-dimethylaniline derivatives
CF3C6H5 (deaerated), rt, 70 h
(100 mM)
N
O
Aux:
O
Aux
CH3
CH3
O
Aux
CF3
O
Aux
O
Aux
CH3
H3C
N
2j
(1 M)
H3C
H3C
H
CH3 H3CO
5gj
28%, d.r. >99:1
OCH3
N
N
N
N
CH3
CH3
CH3
5ec
CH3
5eb
48 h, 93%
5gb
5ed
Scheme 2. (a) Regioselective formation of α-aminoalkyl radical and 1,2,3,4-
26 h, 76%
120 h, 33%
87 h, 27%
THQ forming reaction. (b) Construction of three contiguous stereogenic centers.
O
Aux
CF3
O
Aux
O
Aux
H3CO
F
CH3
Br
CH3
N
N
N
Cleavage of the carbon-nitrogen bond in the acyclic imide
moiety of 1,2,3,4-THQ 5ea was attempted (Scheme 3). The
reaction was carried out by using NaBH4 in THF/H2O at room
temperature to give alcohol 8 and carboxamide 9 in the ratio of
77:23 (Scheme 3a). Alcohol 8 was successfully isolated in 62%
yield. Carboxamide 9 was obtained as a mixture of the 2-
methoxybenzamide auxiliary. Accordingly, we synthesized 9 to
identify the structure by using a different synthetic method (see
SI). Formal [4+2] photo-cycloaddition of α,β-unsaturated imide 1g
with 1-phenylpyrrolidine 2k was conducted to give a mixture of
1,2,3,4-THQ 5gk and unknown by-products which was
subsequently reacted with NaBH4 to achieve the synthesis of a
CH3
CH3
CH3
5gd
5ee
5ef
46 h, 39%
71 h, 51%
72 h, 47%
(iii) Evaluation of substituents on the meta-position of N,N-dimethylaniline derivatives
O
Aux
CH3
O
Aux
H3C
CH3
H3C
CH3
N
N
CH3
1e
As above
1e
F
As above
N
H3C
N
CH3
F
CH3
CH3
5eg
2g
2h
5eh
72 h, 34%
7-F:5-F = 70:30
48 h, 68%
[a] All 1,2,3,4-THQs 5ea-5eg were isolated with the exception of 5eh.
We tried to carry out regioselective generation of α-aminoalkyl
radicals and to introduce three contiguous stereogenic centers in
1,2,3,4-THQs (Scheme 2). The reaction of α,β-unsaturated imide
1e with 2-(N-methylanilino)ethanol (2i) was investigated to
achieve regioselective generation of an α-aminoalkyl radical
followed by formation of 1,2,3,4-THQ 5ei (Scheme 2a). A
mechanism for regioselective formation of α-aminoalkyl radical
would be explained by a stereoelectronic rule (see SI).[42] Next,
we undertook the introduction of three contiguous stereogenic
centers in a 1,2,3,4-THQ. We conducted the reaction of α,β-
unsaturated imide 1g with N,N-diethyl-4-methylaniline (2j) to give
1,2,3,4-THQ 5gj with excellent diastereoselectivity (Scheme 2b).
The relative configuration of 1,2,3,4-THQ 5gj was determined by
NMR, which proved to be 2,3-trans-3,4-trans (see SI).
novel
CF3-containing
benzo[e]indolizidine-5-methanol
10
(Scheme 3b).
(a)
O
HO
O
NH2
CH3
O
NH OCH3
CH3
CH3
NaBH4 (10 equiv.)
+
THF/H2O (4:1),
0 oC to rt, 16 h
N
N
N
CH3
8
CH3
9
CH3
5ea
8:9 = 77:23 (determined by 1H NMR)
Yield of 8 = 62%
thiourea rac−3c (100 mM)
photo-sens. 4g (5 mM)
V-70 (400 mM)
(b)
O
Aux
CF3
N
white LED (λ = 400−780 nm)
1g
(100 mM)
+
CF3C6H5 (deaerated), rt, 70 h
N
O
Aux:
2k
(1 M)
N
5gk
H
(without isolation)
OCH3
HO
CF3
NaBH4 (10 equiv.)
THF/H2O (4:1),
0 oC to rt, 3 h
N
10
14%, d.r. >99:1 (2 steps)
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10.1002/chem.202004186
Chemistry - A European Journal
RESEARCH ARTICLE
Scheme 3. (a) A chemoselective removal of the auxiliary. (b) A synthesis of a
novel CF3-containing benzo[e]indolizidine-5-methanol 10.
photo-excited state of Ir(III) complex 4g* (*Ir(III)) is subjected to
reductive quenching by N,N-dialkylaniline 2 via SET to generate
ox
amine radical cation 2•+ (Ep [2/2•+] = +0.41 V versus Fc/Fc+ in
CH3CN) followed by PT, eventually producing α-aminoalkyl
To understand the initial process of the formal [4+2] photo-
cycloaddition, we carried out quenching experiments of the Ir(III)
complex 4g fluorescence emission with acyclic α,β-unsaturated
imide 1e, N,N-dimethylaniline (2a), and thiourea rac–3c in CH2Cl2
(see SI). Among them, only N,N-dimethylaniline (2a) quenched
Ir(III) complex 4g emission. The Stern-Volmer constants (kqτ) and
the quenching fraction of emission (η) were 2.19 x 105 M−1 and
99.9% for N,N-dimethylaniline (2a), respectively. Then, we
determined the quantum yield by using K3[Fe(C2O4)3] as a
red
radical A and Ir(II) complex. The resulting Ir(II) complex (E1/2
[Ir(III)/Ir(II)] = –1.29 V versus Fc/Fc+ in CH3CN) is oxidized by a
red
large excess of V-70 to form anion radical of V-70 (V-70•–) (E1/2
[V-70/V-70•–] = –1.29 V versus Fc/Fc+ in CH3CN) and converted
to ground state Ir(III) complex 4g. The radical anion of V-70 (V-
70•–) is protonated to generate the hydrazyl radical. On the other
hand, α,β-unsaturated imides 1 (En [1e/1e•–] = –1.31 V versus
Fc/Fc+ in CH3CN) are not subject to the facile reduction caused
by Ir(II) complex in the presence of excess amounts of V-70,
which achieves not only increasing catalytic turnover of Ir(III)
complex 4g, but also prevents formation of the reduced product
of α,β-unsaturated imide 1e. In the thiourea-mediated cycle,
thiourea rac-3c interacts with α,β-unsaturated imide 1e to form
hydrogen-bonded complex B in accordance with a reported
model.[36] The resulting hydrogen-bonded complex B reacts with
α-aminoalkyl radical A via RCA to form α-carbonyl radical
intermediate C. The resulting intermediate C is subjected to
cyclization to give cyclohexadiene π-radical intermediate D which
subsequently undergoes SET followed by PT or HAT with V-
70[25h,25j] to give 1,2,3,4-THQ 5 and the hydrazyl radical where
HAS completes. The resulting hydrazyl radical generated from the
two cycles would be converted to hydrazine via SET followed by
PT or HAT by the reaction with cyclohexadiene π-radical
intermediate D or Ir(II). We could not isolate the resulting
hydrazine because of an unstable compound that leads to
degradation products.[25e,25f,25g,25j]
chemical actinometer.[43,44] As a result, the quantum yield (Φ5ga
)
of the formation of 1,2,3,4-THQ 5ga was determined to be 0.23
(see, SI). The quantum yield did not exceed 1.00, and therefore
we could rule out the non-photochemical radical chain
mechanism. The emission spectrum of the Ir(III) complex 4g was
successfully measured at 77 K in propionitrile/n-butyronitrile (4/5,
v/v), which indicated that the maximum emission peak was
observed at 2.67 eV (464 nm) as 0-0 transition frequency (see SI).
We also carried out cyclic voltammetry (CV) analyses (see SI).
A plausible reaction mechanism is shown in Scheme 4. The
reaction consists of two cycles, i.e., an Ir complex photo-sensitizer
mediated cycle and a thiourea-mediated cycle. Redox potentials
mentioned as follows are the values obtained by CV analyses and
calculated by Rehm-Weller equations (see SI).[44] In the Ir
complex photo-sensitizer-mediated cycle, Ir(III) complex 4g
absorbs light to generate photo-excited state of Ir(III) complex 4g*
red
(*Ir(III)) which is
a strong single electron oxidant (E1/2
[*Ir(III)/Ir(II)] = +1.38 V versus Fc/Fc+ in CH3CN). The resulting
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10.1002/chem.202004186
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RESEARCH ARTICLE
CF3
S
Ar
N
H
N
H
CF3
R4
R4
R1
O
O
O
R2
CH2
R2
R2
Conjugate
addition
N
R3
N
R3
N
H
N
R3
H+ α-Aminoalkyl radical
Amine radical cation
Cyclization
*Ir(III)
4g*
R5
CH3
2•+
A
α-Radical intermediate
CF3
C
hν
CF3
S
SET
R4
S
Ar
N
H
N
H
CF3
Ar
N
N
H
CF3
R2
CH2
R1
H
O
O
O
N
R3
Ir complex photo-sensitizer-mediated cycle
O
O
R2
Thiourea-mediated cycle
N
H
R1
N
H
2
N
R5
R3
CH3
O
CH3
Ir(II)
Cyclohexadiene-π-radical
Hydrogen-bonded complex
Ir(III)
4g
B
D
R4
N
R4
R4
N
N
CF3
R4
N
SET
V-70
V-70
Coordination
S
SET , H+
or
Ar
N2↑
N
H
N
CF3
O
O
N2↑
Degradation products
HAT
H
Degradation products
R1
N
H
O
CH3
rac-3c
R4
N
R4
N
−
V-70•−
1
H+
R1
O
O
R2
N
H
R4
R4
H
R4
N
N
N
R4
R4
R4
N
+
N
R5
N
N
R3
O
H
H
H
SET , H+
or
SET , H+
CH3
Hydrazine
Hydrazyl radical
Hydrazyl radical
(via V-70•−
)
5
or
HAT
HAT
D or Ir(II)
5 or Ir(III)
5 or Ir(III)
D or Ir(II)
Degradation products
Scheme 4. Plausible reaction mechanism.
(Faculty of Chemistry, Materials and Bioengineering, Kansai
University) for his guidance and encouragement. We thank to Prof.
Yoshio Shibagaki (School of Pharmacy, Kitasato University) for
instruction using a lumenscence spectrometer.
Conclusion
The cooperative action of a novel Ir(III) complex photo-
sensitizer, a thiourea, and an azo compound have enabled the
synthesis of structurally diverse 1,2,3,4-THQs possessing
contiguous stereogenic centers in a highly diastereoselective
manner (>99:1) via the visible-light-induced formal [4+2]
cycloaddition of acyclic α,β-unsaturated amides and imides with
N,N-dialkylanilines. The regioselective cyclization of α-carbonyl
radical intermediates and the regioselective generation of α-
aminoalkyl radicals from N,N-dialkylanilines have also been
achieved. A chemoselective cleavage of the acyclic imide moiety
of 1,2,3,4-THQs has been demonstrated. Further studies on
development of a highly enantioselective reaction, elucidation of
photophysical properties of a novel Ir(III) complex, and a
biological assay of 1,2,3,4-THQs are under way.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Nitrogen heterocycles • Photo-reactions • Radical
reactions • Conjugate addition • Aromatic substitution
[1]
[2]
a) A. Kumar, S. Srivastava, G. Gupta, V. Chaturvedi, S. Sinha, R.
Srivastava, ACS Comb. Sci. 2011, 13, 65; b) N. Goli, P. S. Mainkar, S.
S. Kotapalli, K. Tejaswini, R. Ummanni, S. Chandrasekhar, Bioorg. Med.
Chem. Lett. 2017, 27, 1714.
Bromodomain antagonist, see: a) C.-W. Chung, A. W. Dean, J. M.
Woolven, P. Bamborough, J. Med. Chem. 2012, 55, 576; Factor XIa
Inhibitors, see: b) M. L. Quan, P. C. Wong, C. Wang, F. Woerner, J. M.
Smallheer, F. A. Barbera, J. M. Bozarth, R. L. Brown, M. R. Harpel, J. M.
Luettgen, P. E. Morin, T. Peterson, V. Ramamurthy, A. R. Rendina, K. A.
Rossi, C. A. Watson, A. Wei, G. Zhang, D. Seiffert, R. R. Wexler, J. Med.
Acknowledgements
This work was partly supported by JSPS KAKENHI Grants:
JP18K05111 (KI). We are grateful to Prof. Dr. Hitoshi Ishida
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RESEARCH ARTICLE
Chem. 2014, 57, 955; Opioid receptor agonist—antagonists, see: c) A. A.
Harland, L. Yeomans, N. W. Griggs, J. P. Anand, I. D. Pogozheva, E. M.
Jutkiewicz, J. R. Traynor, H. I. Mosberg, J. Med. Chem. 2015, 58, 8952;
Melatonin receptor ligands, see: d) S. Rivara, L. Scalvini, A Lodola, M.
Mor, D.-H. Caignard, P. Delagrange, S. Collina, V. Lucini, F. Scaglione,
L. Furiassi, M. Mari, S. Lucarini, A. Bedini, G. Spadoni, J. Med. Chem.
2018, 61, 3726.
11678; c) W. C. Cronk, O. A. Mukhina, A. G. Kutateladze, Org. Lett. 2016,
18, 3750; d) N. Arai, T. Ohkuma, J. Org. Chem. 2017, 82, 7628.
[18] J. Li, Z. Gu, X. Zhao, B. Qiao, Z. Jiang, Chem. Commun. 2019, 55, 12916.
[19] a) X. Ju, D. Li, W. Li, W. Yu, F. Bian, Adv. Synth. Catal. 2012, 354, 3561;
b) J. Tang, G. Grampp, Y. Liu, B.-X. Wang, F.-F. Tao, L.-J. Wang, X.-Z.
Liang, H.-Q. Xiao, Y.-M. Shen, J. Org. Chem. 2015, 80, 2724; c) Z. Liang,
S. Xu, W. Tian, R. Zhang, Beilstein J. Org. Chem. 2015, 11, 425; d) T. P.
Nicholls, G. E. Constable, J. C. Robertson, M. G. Gardiner, A. C.
Bissember, ACS Catal. 2016, 6, 451; e) J.-T. Guo, D.-C. Yang, Z. Guan,
Y.-H. He, J. Org. Chem. 2017, 82, 1888; f) A. K. Yadav, L. D. S. Yadav,
Tetrahedron Lett. 2017, 58, 552; g) J.-H. Choi, C.-M. Park, Adv. Synth.
Catal. 2018, 360, 3553; h) C.-W. Hsu, H. Sundeń, Org. Lett. 2018, 20,
2051; i) X.-L. Yang, J.-D. Guo, T. Lei, B. Chen, C.-H. Tung, L.-Z. Wu,
Org. Lett. 2018, 20, 2916; j) S. Firoozi, M. Hosseini-Sarvari, M. Koohgard,
Green Chem. 2018, 20, 5540; k) T. P. Nicholls, L. K. Burt, P. V. Simpson,
M. Massi, A. C. Bissember, Dalton Trans. 2019, 48, 12749; l) Z.
Hloušková, M. Klikar, O. Pytela, N. Almonasy, A. Růžička, V. Jandová,
F. Bureš, RSC Adv. 2019, 9, 23797; m) J. Lie, W. Bao, Y. Zhang, Y. Rao,
Org. Biomol. Chem. 2019, 17, 8958.
[3]
[4]
[5]
J. P. Michael, Nat. Prod. Rep. 2003, 20, 476.
B. Nammalwar, R. A. Bunce, Molecules 2014, 19, 204.
a) M. Nishino, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2011, 76,
6447; b) Z. Song, A. P. Antonchick, Tetrahedron 2016, 72, 7715; c) N.
Sakai, S. Matsumoto, Y. Ogiwara, Tetrahedron Lett. 2016, 57, 5449.
a) F. Palacios, C. Alonso, A. Arrieta, F. P. Cossío, J. M. Ezpeleta, M.
Fuertes, G. Rubiales, Eur. J. Org. Chem. 2010, 2091; b) X.-L. Yu, L.
Kuang, S. Chen, X.-L. Zhu, Z.-L. Li, B. Tan, X.-Y. Liu, ACS Catal. 2016,
6, 6182; c) L. Jarrige, F. Blanchard, G. Masson, Angew. Chem. Int. Ed.
2017, 56, 10573; Angew. Chem. 2017, 129, 10709; d) O. Ghashghaei,
C. Masdeu, C. Alonso, F. Palacios, R. Lavilla, Drug Discov. Today
Technol. 2018, 29, 71; e) N. Goli, S. Kallepu, P. S. Mainkar, J. K. Lakshmi,
R. Chegondi, S. Chandrasekhar, J. Org. Chem. 2018, 83, 2244.
Al-mediated reaction, see: a) L. Kværnø, M. Werder, H. Hauser, E. M.
Carreira, Org. Lett. 2005, 7, 1145; Au-mediated reaction, see: b) M. Yan,
T. Jin, Q. Chen, H. E. Ho, T. Fujita, L.-Y. Chen, M. Bao, M.-W. Chen, N.
Asao, Y. Yamamoto, Org. Lett. 2013, 15, 1484; Cu-mediated reaction,
see: c) T. E. Hurst, R. M. Gorman, P. Drouhin, A. Perry, R. J. K. Taylor,
Chem. Eur. J. 2014, 20, 14063; Fe-mediated reaction, see: d) J. Y.
Hwang, A. Y. Ji, S. H. Lee, E. J. Kang, Org. Lett. 2020, 22, 16; Ir-
mediated reaction, see: e) X. Liang, T.-Y. Zhang, X.-Y. Zeng, K. Wei, Y.-
R. Yang, J. Am. Chem. Soc. 2017, 139, 3364; Pd-mediated reaction, see:
f) M. Yoshida, Y. Maeyama, K. Shishido, Tetrahedron 2012, 68, 9962;
Rh-mediated reaction, see: g) K. Okuro, H. Alper, Tetrahedron Lett. 2010,
51, 4959; Sc-mediated reaction, see: h) J. T. Moore, C. Soldi, J. C.
Fettinger, J. T. Shaw, Chem. Sci. 2013, 4, 292; Yb-mediated reaction,
see: i) M. Karikomi, H. Tsukada, T. Toda, Heterocycles 2001, 55, 1249;
Zn-mediated reaction, see: j) T. Guo, B.-H. Yuan, W.-J. Liu, Org. Biomol.
Chem. 2018, 16, 57; Zr-mediated reaction, see: k) A. J. Bird, R. J. K.
Taylor, X. Wei, Synlett 1995, 1237.
[6]
[20] a) X.-M. Zhang, P. S. Mariano, J. Org. Chem. 1991, 56, 1655; b) S.
Bertrand, N. Hoffmann, J.-P. Pete, V. Bulach, Chem. Commun. 1999,
2291; c) S. Bertrand, N. Hoffmann, S. Humbel, J. P. Pete, J. Org. Chem.
2000, 65, 8690; d) S. Marinković, N. Hoffmann, Eur. J. Org. Chem. 2004,
3102; e) S. Marinković, C. Brulé, N. Hoffmann, E. Prost, J.-M. Nuzillard,
V. Bulach, J. Org. Chem. 2004, 69, 1646; f) R. Jahjah, A. Gassama, F.
Dumur, S. Marinković, S. Richert, S. Landgraf, A. Lebrun, C. Cadiou, P.
Sellès, N. Hoffmann, J. Org. Chem. 2011, 76, 7104; g) D. Lenhart, T.
Bach, Beilstein J. Org. Chem. 2014, 10, 890.
[7]
[21] a) M. Nishino, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2011, 76,
6447; b) S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran, M. Rueping, J.
Am. Chem. Soc. 2013, 135, 1823.
[22] X. Shen, Y. Li, Z. Wen, S. Cao, X. Hou, L. Gong, Chem. Sci. 2018, 9,
4562.
[23] S. Kanemasa, Y. Oderaotoshi, H. Yamamoto, J. Tanaka, E. Wada, D. P.
Curran, J. Org. Chem. 1997, 62, 6454.
[24] a) N. Hoffmann, S. Bertrand, S. Marinković, J. Pesch, Pure Appl. Chem.
2006, 78, 2227. b) A. G. Griesbeck, N. Hoffmann, K.-D. Warzecha, Acc.
Chem. Res. 2007, 40, 128.
[8]
[9]
a) N. Gigant, I. Gillaizeau, Org. Lett. 2012, 14, 4622; b) J. Tummatorn, P.
Poonsilp, P. Nimnual, J. Janprasit, C. Thongsornkleeb, S. Ruchirawat,
J. Org. Chem. 2015, 80, 4516.
[25] a) P. S. Engel, W.-X. Wu, J. Am. Chem. Soc. 1989, 111, 1830; b) W. R.
Bowman, H. Heaney, B. M. Jordan, Tetrahedron 1991, 47, 10119; c) D.
P. Curran, H. Yu, H. Liu, Tetrahedron 1994, 50, 7343; d) D. Crich, J.-T.
Hwang, J. Org. Chem. 1998, 63, 2765; e) W. R. Bowman, E. Mann, J.
Parr, J. Chem. Soc., Perkin Trans. 1, 2000, 2991; f) S. M. Allin, W. R. S.
Barton, W. R. Bowman, T. McInally, Tetrahedron Lett. 2001, 42, 7887.;
g) S. M. Allin, W. R. S. Barton, W. R. Bowman, T. McInally, Tetrahedron
Lett. 2002, 43, 4191; h) A. L. J. Beckwith, V. W. Bowry, W. R. Bowman,
E. Mann, J. Parr, J. M. D. Storey, Angew. Chem. Int Ed. 2004, 43, 95;
Angew. Chem. 2004, 116, 97; i) S. M. Allin, W. R. S. Barton, W. R.
Bowman, E. Bridge (née Mann), M. R. J. Elsegood, T. McInally, V.
McKee, Tetrahedron 2008, 64, 7745; j) V. W. Bowry, C. Chatgilialoglu, J.
Org. Chem. 2018, 83, 10037.
a) Fustero, J. Moscardó, D. Jiménez, M. D. Pérez-Carrión, M. Sánchez-
Roselló, C. del Pozo, Chem. Eur. J. 2008, 14, 9868; b) J.-M. Tian, Y.-H.
Yuan, Y.-Y. Xie, S.-Y. Zhang, W.-Q. Ma, F.-M. Zhang, S.-H. Wang, X.-M.
Zhang, Y.-Q. Tu Org. Lett. 2017, 19, 6618.
[10] Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen, P.-F. Xu, B. Wang, Chem. Eur.
J. 2012, 18, 12958.
[11] J. Barluenga, M. Trincado, E. Rubio, J. M. González, J. Am. Chem. Soc.
2004, 126, 3416.
[12] a) J. Yang, H. Wu, L. Shen, Y. Qin, J. Am. Chem. Soc. 2007, 129, 13794;
b) N. Kise, A. Sueyoshi, S. Takeuchi, T. Sakurai, Org. Lett. 2013, 15,
2746.
[13] a) H. Steinhagen, E. J. Corey, Angew. Chem. Int. Ed. 1999, 38, 1928;
Angew. Chem. 1999, 111, 2054; b) J. H. George, R. M. Adlington, Synlett
2008, 2093.
[26] a) W. R. Bowman, J. M. D. Storey, Chem. Soc. Rev. 2007, 36, 1803; b)
B. Zhang, A. Studer, Chem. Soc. Rev. 2015, 44, 3505; c) M. Gurry, F.
Aldabbagh, Org. Biomol. Chem. 2016, 14, 3849.
[14] a) P. Liu, J. H. Seo, S. M. Weinreb, Angew. Chem. Int. Ed. 2010, 49,
2000; Angew. Chem. 2010, 122, 2044; b) Z. Zuo, W. Xie, D. Ma, J. Am.
Chem. Soc. 2010, 132, 13226; c) B. M. Trost, M. Osipov, S. Krüger, Y.
Zhang, Chem. Sci. 2015, 6, 349.
[27] MacMillan’s pioneering study and reviews for Ir(III) photoredox catalysis,
see: a) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; b) C.
K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322;
c) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81,
6898; d) J. Twilton, C. Le, P. Zhang, M. H. Shaw, Ry. W. Evans, D.
W. C. MacMillan, Nat. Rev. 2017, 1, 0052.
[15] R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop, M. F. Lipton, I. J.
Martin, M. A. Mauragis, M. F. Piercey, N. F. Nichols, P. J. K. D. Schreur,
M. W. Smith, M. W. Moon, J. Med. Chem. 1997, 40, 639.
[16] M. Ordóñez, A. Arizpe, F. J. Sayago, A. I. Jiménez, C. Cativiela,
Molecules 2016, 21, 1140.
[28] a) M. P. Sibi, J, Ji. J. Am. Chem. Soc. 1996, 118, 3063; b) U. Iserloh, D.
P. Curran, S. Kanemasa, Tetrahedron: Asymmetry 1999, 10, 2417.
[29] R. P. Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew. Chem. Int. Ed.
2005, 44, 6576; Angew. Chem. 2005, 117, 6734.
[17] a) O. A. Mukhina, D. M. Kuznetsov, T. M. Cowger, A. G. Kutateladze,
Angew. Chem. Int. Ed. 2015, 54, 11516; Angew. Chem. 2015, 127,
[30] M. P. Sibi, K. Itoh, J. Am. Chem. Soc. 2007, 129, 8064.
[31] Y. Chen, C. Liu, L. Wang, Tetrahedron 2019, 75, 130686.
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[32] Deposition Numbers 1984497 for 5aa, 2026397 for 4g, and 1984498 for
5da contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service www.ccdc.cam.ac.uk/structures.
[38] a) I. Stibor, R. Holakovský, A. R. Mustafina, P. Lhoták, P. Collect. Czech.
Chem. Commun. 2004, 69, 365. b) X.-G. Liu, J.-J. Jiang, M. Shi,
Tetrahedron: Asymmetry 2007, 18, 2773. Curran’s pioneering study of
diaryl urea catalysis in synthetic organic chemistry, see: c) D. P. Curran,
L. H. Kuo, J. Org. Chem. 1994, 59, 3259.
[33] D. A. Evans, S. G. Nelson, J. Am. Chem. Soc. 1997, 119, 6452.
[34] M. P. Sibi, N. Prabagaran, S. G. Ghorpade, C. P. Jasperse, J. Am. Chem.
Soc. 2003, 125, 11796.
[39] a) G. Jakab, C. Tancon, Z. Zhang, K. M. Lippert, P. R. Schreiner, Org.
Lett. 2012, 14, 1724. b) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289.
[40] Z. Liu, L. Quin, S. Z. Zard, Org. Lett. 2014, 10, 2704.
[41] X. Zhang, S.-R. Yeh, S. Hong, M. Freccero, A. Albini, D. E. Falvey, P. S.
Mariano, J. Am. Chem. Soc. 1994, 116, 4211.
[35] J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959.
[36] T. Inokuma, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2006, 128, 9413.
[37] The use of chiral thioureas in photochemical reactions, see: a) N.
Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi, J. Sivaguru, Angew.
Chem. Int. Ed. 2014, 53, 5604; Angew. Chem. 2014, 126, 5710. b) F.
Mayr, R. Brimioulle, T. Bach, J. Org. Chem. 2016, 81, 6965. c) F. Mayr,
L.-M. Mohr, E. Rodriguez, T. Bach, Synthesis 2017, 49, 5238. The use
of thioureas in photochemical reactions, see: R. Telmesani, S. H. Park,
T. Lynch-Colameta, A. B. Beeler, Angew. Chem. Int. Ed. 2015, 54,
11521; Angew. Chem. 2015, 127, 10709.
[42] a) F. D. Lewis, T.-I. Ho, J. Am. Chem. Soc. 1980, 102, 1751; b) F. D.
Lewis, Acc. Chem. Res. 1986, 19, 401.
[43] M. Montalti, A. Credi, L. Prodi, M. T. Gandolfi, Handbook of
Photochemistry, Third Edition, CSR Press, 2006, 601.
[44] G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowls, Nature 2016,
539, 268.
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Entry for the Table of Contents
COMMUNICATION
Ir(III) complex photo-sens.
Cooperative action
Kennosuke Itoh*, Shun-ichi Nagao, Ken
Tokunaga, Shigeto Hirayama, Fumika
Karaki, Takaaki Mizuguchi, Kenichiro
Nagai, Noriko Sato, Mitsuaki Suzuki,
Masashi Hashimoto, Hideaki Fujii*
O
N
−BF4
CF3
Visible light
Ir(III) complex photo-sens.
Removal of
auxiliary
F
Acyclic α,β-unsaturated carbonyls
HO
O
NH OCH3
R1
OCH3
N
R2
Thiourea
O
O
R3
R2
R3 Azo compound
NaBH4
R2
R4
N
F
F
R1
+
N
Ir
N
N
OCH3
N
H
CF3C6H5 (deaerated), rt
THF/H2O, rt
R3
N
OCH3
R3
R5
R5
24 examples
Up to 93% yield, >99:1 d.r.
F
CF3
Page No. – Page No.
Formal [4+2] Reaction: The cooperative action of a novel Ir(III) complex photo-
sensitizer, a thiourea, and an azo compound enables visible-light-induced formal
[4+2] cycloaddition of acyclic α,β-unsaturated amides and imides with N,N-
dialkylanilines to synthesize structurally diverse 1,2,3,4-tetrahydroquinolines
possessing contiguous stereogenic centers in a highly diastereoselective manner
(>99:1). A chemoselective removal of the auxiliary has been achieved.
Keywords: Nitrogen heterocycles
Photo-reactions • Radical reactions •
•
Conjugate
addition
•
Aromatic
substitution
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