Visible-Light-Initiated Cascade Reaction of 2-Isothiocyanatonaphthalenes and Amines under Additive- and External Photocatalyst-Free and Mild Conditions

Article abstract of DOI:10.1002/adsc.202001002

A simple and efficient visible-light-initiated cascade reaction of 2-isothiocyanatonaphthalenes and amines with ambient dioxygen as the sole oxidant under additive-, external photocatalyst-free and ambient conditions was developed. 38 Examples of N-substituted naphtho[2,1-d]thiazol-2-amines were regioselectively constructed in good to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202001002

Title: Visible-light-initiated Cascade Reaction of 2-
Isothiocyanatonaphthalenes and Amines under Additive-,
External Photocatalyst-Free and Mild Conditions
Authors: Wen-Hu Bao, Zheng Wang, Zhong Cao, Xin-Chang Wang,
Xin-Ran Ma, Xian-Yong Yu, and Wei-Min He
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001002
Link to VoR: https://doi.org/10.1002/adsc.202001002

10.1002/adsc.202001002
Advanced Synthesis & Catalysis
Full Paper
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Visible-Light-Initiated
Cascade
Reaction
of
2-
Isothiocyanatonaphthalenes and Amines under Additive- and
External Photocatalyst-Free and Mild Conditions
Wen-Hu Baoa, Zheng Wanga, Zhong Caob, Xin-Chang Wanga, Xin-Ran Maa, Xian-
Yong Yuc and Wei-Min Hea*
a
Department of Chemistry, Hunan University of Science and Engineering, Yongzhou, 425100, China
Fax: (+86)-746-6381166; phone: (+86)-018175151053; e-mail: weiminhe2016@yeah.net
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, Changsha University
b
of Science and Technology, Changsha 410114, China
School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, China
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A simple and efficient visible-light-initiated naphtho[2,1-d]thiazol-2-amines
were
regioselectively
cascade reaction of 2-isothiocyanatonaphthalenes and constructed in good to excellent yields.
amines with ambient dioxygen as the sole oxidant under
Keywords: photocatalyst-free • radical cascade reaction •
visible-light • metal-free • photocatalysis
additive-, external photocatalyst-free and ambient conditions
was developed. 38 Examples of N-substituted
naphtho[2,1-d]thiazol-2-amines through cascade
reaction of 2-isothiocyanatonaphthalenes and
aliphatic secondary amines was reported by Lei and
colleagues in 2017 (Scheme 1a).[4a] However, the
practicability and environmental friendliness of the
cross-coupling reaction are compromised by the need
for a large excess of expensive electrolyte and tedious
nitrogen protection. Moreover, the amine substrates
are incompatible with aliphatic primary amines and
aromatic amines. In the same year, Zhang and Fan
disclosed molecular iodine-catalyzed oxidative
cascade reactions of 2-isothiocyanatobenzenes with
primary or secondary using molecular oxygen as the
Introduction
Molecular oxygen is a preferred ideal oxidant
given its high abundance, low cost and
environmentally benign virtues, and it could be easily
removed after the oxidative process. The visible-light-
initiated oxidative reaction with molecular oxygen as
an oxidant is undoubtedly an ideal and promising
alternative to traditional oxidative procedures.[1]
However, precious and/or toxic transition-metals or
eco-unfriendly organic photocatalysts are necessary in
most photocatalytic oxidative processes, which not
only produce wastes, but also increase production
cost, leading to tedious isolation and purification
procedures and environmental issues. Therefore, the
development of novel visible-light-initiated oxidation
reactions which could be performed employing
molecular oxygen as the sole oxidant without the need
for an external photocatalyst is highly desirable.
o
sole oxidant in chlorobenzene at 120 C (Scheme
1b).[4b] However, the utilization of molecular oxygen
in the presence of toxic chlorobenzene at high
temperature results in a potentially flammable and
explosive mixture, which greatly restricts the
application of the reaction in chemical and
pharmaceutical industry. As a result, it is highly
desirable to open up general synthetic protocols to
various N-substituted naphtho[2,1-d]thiazol-2-amines
under additive-free and ambient conditions.
N-substituted naphtho[2,1-d]thiazol-2-amines are
extremely
valuable
structural
motifs
for
pharmaceutical and materials chemistry.[2] However,
compared with the well-established methods for
synthesizing 2-aminobenzothiazoles,[3] protocols for
the direct construction of such molecules are still
rare.[4] Among these synthetic methodologies, the
As a part of our ongoing interest in the
development of green synthetic methods[5] , we herein
disclose a clean and green method for the construct of
various N-substituted naphtho[2,1-d]thiazol-2-amines
via visible-light initiated (the 6th Principle) oxidative
cascade reaction (the 2nd and 8th Principle)[6] of 2-
isothiocyanatonaphthalenes and simple amines with
ambient molecular oxygen as an oxidant (the 7th
Principle) under additive-, external photocatalyst-free
one-pot
cascade
reaction
of
2-
isothiocyanatonaphthalenes and simple amines is the
best choice for attaining atom- and step economy as
well as the cheap and easily available raw materials.
Elegant electrochemical synthesis of N-substituted
1
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10.1002/adsc.202001002
Advanced Synthesis & Catalysis
(the 1st Principle) and ambient conditions (Scheme 68% NMR yield of 3aa (entry 3). Further
1c).
examination of various solvents (entries 8 - 13)
indicated that DMSO was the best reaction medium
for the current photocatalytic reaction (entry 12). A
lower yield of 3aa was obtained by changing
molecular oxygen to ambient air (entry 14). When the
reaction was conducted under a nitrogen atmosphere,
no product was detected (entry 15). It was noteworthy
that no product 3aa was observed in the absence of
visible-light irradiation even when the reaction
o
continued at 120 C for 24 h (entry 16). No reaction
took place in the dark (entry 17).
Table 2. Reaction Scopea
Scheme 1. Synthesis of N-substituted Naphtho[2,1-
d]thiazol-2-amines
Results and Discussion
Table 1. Optimization of reaction conditionsa
Entry
1
Light Source
375-380 nm
380-385 nm
385-390 nm
390-395 nm
395-400 nm
400-405 nm
405-410 nm
385-390 nm
385-390 nm
385-390 nm
385-390 nm
385-390 nm
385-390 nm
385-390 nm
385-390 nm
--
Solvent
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
Yieldb
52%
57%
68%
59%
54%
46%
42%
51%
72%
35%
Trace
93%
33%
76%
N.D.
N.D.
N.D.
2
3
4
5
6
7
8
MeCN
9
EtOH
10
11
12
13
14c
15d
16e
17f
DCE
DMSO
DMF
DMSO
DMSO
DMSO
--
DMSO
[a] Conditions: 1a (0.2 mmol), 2a (0.26 mmol), solvent (1 mL), O2
balloon, 10 W LED, rt, 12 h
[b]
Estimated by 1H NMR using diethyl phthalate as internal
reference.
[c] Under ambient air atmosphere.
[d] Under nitrogen atmosphere.
[e] 120 oC, 24 h. N.D.: no detected.
[f] In the dark.
[a] 1 (0.3 mmol), 2 (0.39 mmol), DMSO (1.5 mL), O2 balloon, 10
W LED (385-390 nm), rt, 12 h.
With the optimal reaction conditions in hand
(Table 1, entry 12), the substrate scope of the current
reaction was evaluated (Table 2). Pleasingly,
At the outset of this study, the reaction of 2-
isothiocyanatonaphthalene (1a) and p-toluidine (2a)
was carried out for the screening of reaction
parameters (Table 1). Performing the model reaction
with molecular oxygen in 1,4-dioxane under the
irradiation of a 10 W LED (375 – 380 nm) at ambient
temperature for 12 h afforded the target product 3aa
in 52% NMR yield (Table 1, entry 1). Next, the effect
of visible-light source on the template reaction was
explored (entries 2-7). Performing the reaction with
the irradiation wavelength of 385 - 390 nm led to a
substituted phenylamines with
a
range of
synthetically important functional-groups smoothly
underwent the photocatalytic cascade reaction to form
the target products (3aa - 3av) in good to excellent
yields. Neither the electronic effect nor steric
hindrance effect of the substituent group in
phenylamines had a considerable influence on the
present transformation. The oxidizable methylthio
group containing phenylamine generally prone to over
2
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10.1002/adsc.202001002
Advanced Synthesis & Catalysis
oxidation underwent visible-light-initiated oxidative
cascade reaction facilely to deliver the desired
product in 79% yield (3ai). Polycyclic and
heteroaromatic substituted amines could participate in
the photocatalytic transformation efficiently providing
the target products in good yields (3aw - 3ay).
Aliphatic primary amines with various carbon chain
lengths and isomeric structures had little influence on
the outcome of the current reaction and delivered the
corresponding products in 70 - 86% yields (3az -
3aF). The present protocol could be extended to the
secondary amine substrates, affording the desired
products with good yields (3aG - 3aJ). As expected,
2-isothiocyanatonaphthalene bearing an electron-rich
methoxy group or electron-deficient bromo group was
found to be appropriate substrates to provide the
desired products 3ba and 3ca in 81% and 86% yields,
respectively.
proceeds via a cascade nucleophilic addition and
cyclization reaction.
Figure 2 Light Irradiation On–Off Experiment
The
visible-light
irradiation
on-off
experiment of the present cascade reaction
revealed that the current reaction was fully
suppressed in the absence of visible light
irradiation (Figure 2). These experimental results
proved the light-dependency of the current
transformation.
Scheme 2. Gram-scale reaction
To demonstrate the practicability of the
photocatalytic reaction, a scale-up reaction (5 mmol)
was conducted (Scheme 2). The isolated yield was
similar to that from the small-scale reaction.
Importantly, increasing the concentration of 1a from
0.2 M to 3 M was feasible. The scalability of the
developed process combined with the simple
operational procedure made this protocol very
attractive for organic synthesis and industry
production.
Scheme 3. Control Experiments
Figure 3 UV/Vis Absorption Experiment
Several control experiments were carried out to
understand the reaction mechanism of the present
photocatalytic reaction (Scheme 3). When two equiv.
of radical scavenger (TEMPO or BHT) were added
into the photocatalytic reaction system, the desired
transformation was totally suppressed (Scheme 3a).
These results suggested that the present photocatalytic
reaction proceeds through a free-radical pathway. The
treatment of 9,10-dimethylanthracene (5a) under the
Figure 1 Time course for the conversion of 1a
The effect of visible-light irradiation time on the
conversion of 2-isothiocyanatonaphthalene (1a) was
then investigated under the optimal reaction
conditions. As depicted in Figure 1, in the primary
reaction stage of 4 hours, both 28% yield of 3aa and
62% yield of 1-(naphthalen-2-yl)-3-(p-tolyl)thiourea
(4a) were formed with 90% conversion of the
substrate 1a. After cascade reaction for 8 hours, 69%
yield of 3aa and 31% yield of 4a based on complete
optimal
reaction
conditions
delivered
the
endoperoxide product (5b) via [4+2] cycloaddition
reaction, in which singlet oxygen (1O2) was probably
involved (Scheme 3b).[7] The experimental results of
ultraviolet-visible absorption-spectra showed that the
products 3 could absorb visible light at 385 - 390 nm
1
conversion of 1a were detected by H NMR. As the
oxidative reaction proceeded 12 hours, 4a was fully
converted into 3aa. These results revealed that the
visible-light-initiated oxidative reaction most likely
3
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10.1002/adsc.202001002
Advanced Synthesis & Catalysis
and might serve as a photocatalyst (Figure 3), thus scalability, the present method process could be
avoiding the employment of an external photocatalyst. expected to be ideal for synthetic chemistry and
pharmaceutical chemistry.
Experimental Section
Typical Procedure for the Synthesis of
Naphtho[2,1-d]thiazol-2-amines 3
1 (0.3 mmol), 2 (0.39 mmol) and DMSO (1.5
mL) was added to a 10 mL quartz tube with an
Scheme 4. Proposed Reaction Mechanism
O2 balloon at room temperature under the
irradiation of 10 W LED lamps (385 - 390 nm)
According to the above observations and
for 12 h, the reaction was monitored by TLC.
relevant literature reports,[4a, 4b, 8] a plausible
Upon completion, water (20 mL) was added
reaction mechanism for the cascade reaction is
to the reaction mixture, it was extracted with
proposed in Scheme 4. At first, the thiourea
intermediate (4) was generated through in-situ
nucleophilic addition of amine (2) to 2-
isothiocyanatonaphthalene (1). Secondly, the
product 3 was excited by 385 - 390 nm
wavelength of visible-light irradiation to produce
the singlet excited state product 3*, which then
underwent an energy transfer process (ET) with
ground state triplet oxygen (3O2) to generate an
active excited state singlet oxygen (1O2) with the
reproduction of ground state products 3. The
active singlet oxygen reacted with intermediate 4
through a single electron transfer (SET) process
EtOAc (5 mL x 3) and the organic extracts
were dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The
crude product was purified by column
chromatography on silica gel to obtain product
3
.
Acknowledgements
We are grateful for financial support from the
Hunan Provincial Natural Science Foundation of
China (Nos. 2019JJ50193 and 2019JJ20008).
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In conclusion, a novel visible-light-initiated
oxidative
cascade
reaction
of
2-
isothiocyanatonaphthalenes and amines with
molecular oxygen as the sole oxidant under
additive-, external photocatalyst-free and ambient
conditions was developed. A wide range of N-
substituted naphtho[2,1-d]thiazol-2-amines were
constructed in good to excellent yields. The
present reaction proceeds under clean and mild
reaction conditions with high chemo- and region-
selectivity and a broad substrate scope (primary
and secondary amines), as well as high functional
group compatibility. In sharp contrast to the
previous oxidative synthetic strategies, the
oxidizable methylthio group and heteroaromatic
amines were also well-tolerated. Given the easily
available and inexpensive raw materials, mild
conditions, simple operational procedure and high
4
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10.1002/adsc.202001002
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.202001002
Advanced Synthesis & Catalysis
Full Paper
Visible-light-initiated Cascade Reaction of 2-
Isothiocyanatonaphthalenes and Amines under
Additive-, External Photocatalyst-Free and Mild
Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
A simple and efficient visible-light-initiated
oxidative
cascade
reaction
of
2-
isothiocyanatonaphthalenes and amines with
dioxygen under additive-, external photosensitizer-
free and ambient conditions was developed.
6
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