A Cu2O/TBAB-promoted approach to synthesize heteroaromatic 2-Amines: Via one-pot cyclization of aryl isothiocyanates with ortho-substituted amines in water

Article abstract of DOI:10.1039/d0ob01431a

An efficient approach to synthesize heteroaromatic 2-Amines from one-pot desulfurization/dehydrogenative cyclization of aryl isothiocyanates with ortho-substituted amines in water was developed. This approach tolerated a wide range of functional groups on

Full text of DOI:10.1039/d0ob01431a

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DOI: 10.1039/D0OB01431A
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Cu2O/TBAB-promoted approach to heteroaromatic 2-amine via
one-pot cyclization of aryl isothiocyanates with ortho-substituted
amines in water
Received 00th January 20xx,
Accepted 00th January 20xx
Jinli Zhanga,b*, Ling Chena, Yibo Donga, Jinchen Yangb and Yangjie Wua,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient approach to heteroaromatic 2-amine from one-pot desulfurization/dehydrogenative cyclization of aryl
isothiocyanates with ortho-substituted amines in water was developed. This access tolerated a wide range of functional
groups on the aromatic ring, providing a practical and environment-friendly process to heteroaromatic 2-amine in
moderate to excellent yields. A plausible mechanism was proposed and the role of TBAB and Cu2O in the present strategy
was suggested with the help of ESI mass spectrometry.
required both in the intramolecular and intermolecular cyclization.
Recently, microwave-assisted,26 electro-oxidation reduction,27
photocatalysis28 or ultrasound29 techniques are also used for this
kind of reaction.
However, most of the available methods have more or less
disadvantages, such as expensive or toxic metal-based reagents
that require stoichiometry or larger amounts, and their careful
post-treatment, and the solvent is not enough environmental
protection, limited substrate applicability, multi-step reaction, high
temperature, long reaction time and low yields.
Based on the above discussion and our continued efforts for
developing efficient heterocyclization reactions,30 we explored an
one-pot desulfurization/dehydrogenative cyclization of aryl
isothiocyanates with ortho-substituted amines to the corresponding
2-amino benzo[d]oxazole, benzo[d]thiazole, naphtho[2,3-d]oxazole,
and benzoxazin derivatives in water. From the viewpoint of green
and sustainable chemistry, water was extensively used as an
environmentally friendly solvent to realize the construction of new
C-C/C-X bond in one-pot with highly efficiency and facility in this
study. Although Fan and co-workers10c has developed FeCl3-
catalyzed similar synthesis, the present work has the advantage of
wide functional groups tolerance, high yields and novel dual-
catalysis mode of TBAB/Cu2O.
Introduction
Heteroarylamines is a class of building block that have received
widespread attention from synthetic chemists because of their role
in the pharmaceutical industry and functional materials.1 2-
Aminobenzoxazole derivatives are ubiquitous scaffolds in a wide
variety of therapeutic agents for a treatment of CNS disorders,2
insomnia,3 Alzheimer’s disease,4 and significant targets in
combinatorial approaches.5 Some 2-aminobenzothiazole derivative
pesticides have been experimentally protected against irradiation
on plasmid DNA.6
Given the importance of the 2-N-substituted azole motifs in
biological medicinal chemistry and material chemistry, a number of
methods for the synthesis of 2-amino benzoxazoles/benzothiazoles
have been developed. Generally, this backbone was obtained via
three classical routes: direct functionalization of C-H/C-X bond of
heterocycles; intramolecular desulfurization cyclization of N-(2-
hydroxyphenyl)-N’-arylthiourea,7 N-Arylthioureas,8 and o-phenolic
amidines;9 and intermolecular cyclization of isothiocyanate with o-
thio/hydroxy/amino/halo anilines.10 Direct functionalization of C-
H/C-X bond of benzoxazoles/benzothiazole often needed a noble
metals or
a
proper oxidant under high temperature.
Desulfurization/dehydrogenative reagents/catalysts, such as
AgNO3,11 NiO,12 HgO,13 FeCl3,10c,14 and CuCl2,15 KO2,16 Ph3BiCl2,17
CF3CO2H18 and TfOH,19 TsCl/NaOH,20 LiOH/H2O2,21 TBAI/H2O2,22
polymer-supported carbodiimides,23 hypervalent iodine (III),24
and1,10-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT),25 are
Results and discussion
Initially, 2-aminophenol (1a) and phenyl isothiocyanate (2a) was
selected as model substrates to optimize the reaction conditions
(Table 1). Control experiments revealed that a metal catalyst and a
phase transfer catalyst were essential to the reaction, and only a
24% or 51% yield was obtained in the absence either of them (Table
1, entries 1-3). To our delight, by using Cu2O as metal catalyst and
TBAB as phase transfer catalyst, the reaction proceeded well,
affording the desired product N-phenylbenzoxazole-2-amine 3aa in
73% isolated yield in H2O at 80 °C after 5 h in a sealed tube (entry 4).
a Henan Key Laboratory of Chemical Biology and Organic Chemistry Key
Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University,
Zhengzhou, 450052, P.R. China
b College of Chemistry, Green Catalytic Center, Zhengzhou University, Zhengzhou
450001, P. R. China
*Corresponding author, E-mail: jinli@zzu.edu.cn
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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aReaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), copper catalyst (0.20
When the amounts of phenyl isothiocyanate (2a) were
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mmol), additive (0.20 mmol), solvent (1.5 mL) at 80 °C for 5 h, under air
DOI: 10.1039/D0OB01431A
increased from 0.2 equiv. to 0.3 equiv., the yield of 3aa increased to
99% (entry 5). Further study showed that the air atmosphere has
significant effect on the yield. When the reaction was carried out
under open air, O2 or Ar, 3aa was obtained in 83%, 60% and 64%
isolated yield, respectively (entries 6-8). Next, various copper salts
such as CuBr, CuI, CuCl, CuO, CuCl2, CuSO4, and Cu(OAc)2 were
screened (entries 9-15), in which Cu2O was found to be the best
choice giving 99% yield (entry 5). Other additives such as TBAB or
TBAC were also estimated to improve the solubility, and diminished
yields of 3aa were obtained (entries 16-17). Remarkably, 82% yield
of 3aa could be detected when Et3N was used instead of TBAB
(entry 18). Different bases were examined subsequently, 66-92%
isolated yield of 3aa were obtained in basic conditions (entries 19-
23). In addition, the yield of 3aa dropped with lowering the
temperature of the reaction to 60 °C (entry 24) or increasing to 100
°C (entry 25). And the yield of 3aa decreased in H2O on shorting the
reaction time to 2 h (or 3 h) or prolonging to 6h (entry 26).
atmosphere in sealed condition. bYield of isolated products. cThe reaction was
finished in 2 h. dThe reaction was finished in 3h. eThe reaction was finished in 6 h.
Thus, the optimal reaction conditions for the construction of C-
C/C-X (O, N) bonds were obtained with 2-aminophenol 1a (0.2
mmol), phenyl isothiocyanate 2a (0.3 mmol), cuprous oxide (0.2
mmol) and TBAB (0.20 mmol), in H2O (1.5 mL) at 80 °C for 5 h under
air atmosphere in sealed condition (entry 5).
With the optimal conditions in hand, we then evaluated the
scope and limitation of substrates and the results are summarized
in Table 2-4. Generally, several 2-aminophenol 1a-1k and phenyl
isothiocyanate 2a-2K or aliphatic isothiocyanates (2l, 2m) could be
amenable for the reaction and afford the corresponding products in
moderate to excellent yields ranging from 37% to 99%. Various
functional groups such as CH3, CH3O, F, Cl, Br, I, CF3, NO2, and 1-
naphthyl etc. were all well tolerated.
As shown in Table 2, the scope of the reaction of 1a with
different phenyl isothiocyanate 2a-2k was examined firstly. All
reactions proceeded well under the optimal conditions. Phenyl
isothiocyanates bearing electron-donating (o-CH3 (2b), m-CH3 (2c),
p-CH3 (2d), p-OMe (2g)) or electron-withdrawing groups (p-F (2e), p-
CF3 (2h), and p-NO2 (2k)) reacted efficiently with 1a in H2O,
affording N-arylbenzoxazole-2-amine 3aa-3ak in good to excellent
yields. Notably, the substituents residing at different positions on
the phenyl ring of phenyl isothiocyanates were tolerant to the
reaction, as in the cases of 3ab-3ad. And the substituents at the
ortho-position (3ab) gave relatively lower yields, indicating that the
steric hindrance have no significant effects on the reaction yield.
However, the obvious steric hindrance was observed in case of 3ai,
the corresponding N-(naphthalen-1-yl)-1,3-benzoxazole-2-amine 3ai
was obtained only in 65% yield when 1-naphthyl isothiocyanate 2i
was subjected to the reaction conditions. The alkyl isothiocyanates
such as isopropyl isothiocyanate 2l and benzyl isothiocyanate 2m
were also suitable substrate for the TBAB/Cu2O promoted one-pot
cyclization. The desired product 3al and 3am were obtained in 63%
and 83% isolated yields, respectively.
Table 1 Optimization of reaction conditions.a, b
N
C S
OH
N
copper
H
N
base
t
+
O
NH2
H2O
T
2a
3aa
1a
ratio of
yield
(%)b
entrya
copper
additive
atmosphere
T/oC
1a:2a
1
--
1:1
--
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
open air
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
19
24
51
73
99
83
60
64
9
2
--
1:1
TBAB
--
3
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuBr
CuI
1:1
4
1:1
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
6
7
O2
8
Ar
We then turned our attention to investigating the substrate
generality of 2-aminophenol derivates 1a-1k. It was pleasing to find
that the 5-substituted substruates such as 2-amino-5-methylphenol
1b, 2-amino-5-fluorophenol 1c, 2-amino-5-chlorophenol 1d, 2-
amino-5-bromophenol 1e, participated in this reaction very well,
yielding the corresponding products in 51-99% isolated yields.
9
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
35
38
70
14
24
46
90
87
82
66
75
92
83
92
81
90
CuCl
CuO
CuCl2
CuSO4
Generally,
electron-neutral
and
electron-rich
phenyl
isothiocyanates displayed higher reactivity than the electron-
deficient ones (3ba and 3bd vs 3bf; 3ba and 3ca vs 3cg; 3ea and 3ed
vs 3ee and 3ej) in this conditions. In particular, 2-aminophenol
substrates 1a-1e with electron-donating groups on the benzene ring
at 5-position could afford higher yields than those bearing electron-
withdrawing groups, as shown in cases of 3aa, 3ba, 3ca, 3da and
3ea. The reason for the high yield of 3ea could be attributed to the
weak inductive effect of the electron-withdrawing group (Br) in 5-
position.
Furthermore, 3-substituted substruates such as 2-amino-3-
methylphenol 1f, 2-amino-3-nitrophenol 1g, were also found to be
compatible, which provided 3fa, 3fd, 3fe, 3ff, 3fg and 3ga in
excellent yields except 3ga, respectively. The inferior yields of 3ga
were observed when 1g reacted with 2a under optimal conditions,
probably as a result of strong inductive effect of the electron-
withdrawing group (NO2). Particularly, 3fb was obtained in 53%
isolated yield, presumably due to the strong effect of steric
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
TBAC
Et3N
t-BuOK
K2CO3
KHCO3
K3PO4
NaOAc
TBAB
TBAB
86c;
93d; 96e
26
Cu2O
1:1.5
TBAB
air, sealed
80
2 | J. Name., 2012, 00, 1-3
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hindrance. Interestingly, 1-naphthyl isothiocyanate 2i gave the para-position of the phenyl isothiocyanate were observed, steric
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desired 4-methyl-N-(naphthalene-1-yl)-1,3-benzoxazole-2-amine 3fi hindrance effect is not obvious, as shown in the case of 3ka, 3ki,
DOI: 10.1039/D0OB01431A
in moderate yield (63%), which proved an effective and universal 3kg and 3kk. It was found that electron-rich phenyl isothiocyanate
method to install heteroaromatic motifs.
could afford higher yields than the electron-deficent ones.
To further extend the scope of the reaction, 4-substituted
Notably, the position of the substituents on the aromatic rings
substruates such as 2-amino-4-methoxyphenol 1h, 2-amino-4- of the 2-aminophenols had little effect as indicated in 3ba vs 3fa,
chlorophenol 1i, 2-amino-4-bromophenol 1j, were also tested 3da vs 3ia, 3bg vs 3fg, 3be vs 3fe, etc. Moreover, both substrates
under the optimal conditions. All worked well to afford the with electron-withdrawing halogen substituents residing at
corresponding benzoxazole-2-amine in 37%-93% isolated yields. different positions on the phenyl ring such as F, Cl, Br and I could
The poor yield of 5-methoxy-N-phenyl-1,3-benzoxazole-2-amine undergo a facile synthesis, giving the desired products 3ae–3jg in
3ha (37%) is mainly because this reaction proceeds not very well good yields (17 products, such as 3ae, 3be, 3bf, 3ca, 3cg, 3da, 3ea,
under an acid condition (pH = 5-6). And the poor yield of 3ha was 3ed, 3ee, 3ej, 3fe, 3ff, 3ia, 3ie, 3ig, 3jg, 3ii, 51–94% isolated yields,
attribute to the demethylation of methoxy group31 of product 3ha, respectively). The halogen substituted products were beneficial for
the dimerization of demethylated product 5-hydroxyl-N-phenyl-1,3- further functionalization.
benzoxazole-2-amine ([M+H] = 227.1, detected by HPLC-MS),
On the other hand, 2-aminophenol (1a) was replaced with 2-
unsuccessful cyclization caused by the poor nucleophilic ability of aminothiophenol (4a) to explore the scope of this reaction. As
hydroxyl group under TBAB conditions (see SI). Furthermore, the shown in Table 3, the reaction of 4a with phenyl isothiocyanate 2a-
desired 5-chloro-N-(naphthalene-1-yl)-1,3-benzoxazole-2-amine 3ii 2d could proceed smoothly to give the corresponding product 5aa-
(93%) and 5-bromo-N-(naphthalen-1-yl)-1,3-benzoxazol-2-amine 3ji 5ad in excellent yields (61-99%). Furthermore, no obvious steric
(83%) was gained in excellent yields when 1-naphthyl hindrance effects were observed in case of 5ab, the reason for the
isothiocyanate 2i reacted with 1i or 1j.
low yield of 5ad may be caused by conjugation effect.
Table Substrate scope for the synthesis of N-arylbenzoxazole-2- Table 3 Substrate scope for the synthesis of N-aryl-1,3-
2
amine derivativesa,b
benzothiazo-
R1
NCS
le-2-amine derivativesa,b
R1
NH2
Cu2O, TBAB
N
H
NCS
N
+
NH2
R2
OH
Cu2O, TBAB
N
S
O
air, H2O, 80 oC, 5h
H
R2
N
1a-1k
3aa-3kk
2a-2m
SH
R2
air, H2O, 80 oC, 5h
R2
4a
R1
5aa-5ad
2a-2d
N
O
R2=H
N
O
H
N
H
R2
N
N
R2
H
N
R2
R1
R1=CH3 R2=H
R1=CH3 R2=CH3
R1=CH3 R2=F
R1=CH3 R2=Cl
3ba 99%
3bd 99%
3be 90%
3bf 76%
O
3aa 99%
N
S
N
S
H
N
R2=CH3 3ad 90%
R1=CH3 R2=H
3fa 94%
H
N
R2=F
3ae 94%
R1=CH3 R2=CH3 3fd 95%
R2=OCH3 3ag 84%
R2=CF3 3ah 95%
R2=NO2 3ak 63%
R1=CH3 R2=F
R1=CH3 R2=Cl
3fe 99%
3ff 91%
5aa 99%
5ab 94%
R1=CH3 R2=OCH3 3bg 77%
R1=F
R2=H
R2=OCH3 3cg 51%
3ca 67%
R1=CH3 R2=OCH3 3fg 89%
R1=F
R1=NO2 R2=H
3ga 84c
%
H
N
N
S
N
H
N
R1=Cl
R1=Br
R1=Br
R1=Br
R1=Br
R2=H
R2=H
R2=CH3
R2=F
3da 75%
3ea 98%
3ed 81%
3ee 66%
3ej 67%
N
H
S
N
O
R1
5ac 91%
5ad 61%
N
H
N
O
R2
3ac 90%
aReaction conditions: 2-aminothiophenol (0.20 mmol), Phenyl isothiocyanate
(0.30 mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80 °C for 5 h,
under air atmosphere in sealed condition. bYield of isolated products.
R2=I
R1=OCH3 R2=H
3ha 37%
3ia 89%
3ie 85%
N
H
R1=Cl
R1=Cl
R1=Cl
R1=Br
R2=H
R2=F
R2=OCH3 3ig 85%
R2=OCH3 3jg 90%
N
O
N
H
N
O
R2
3ai 65%
R2=H
3ka 58c
%
Finally, to demonstrate the generality of this approach, other
substruate such as 2-aminobenzyl alcohol (6a), and 2-(2-
aminophenyl) ethan-1-ol (8a) were then applied as the next
objective of our investigation. Fortunately, 6a reacted very well
with phenyl isothiocyanate 2a, 2d and 2e to afford the
corresponding 1,3-benzoxazin derivatives 7aa, 7ad, 7ae and 9aa in
70%, 52%, 67% and 20% isolated yields, respectively, indicating the
general utility of this transformation as listed in Table 4.
R2=OCH3 3kg 70%
N
R2=NO2
N
3kk 57%
NH
O
R1
Br
R2
3al 63%
N
H
N
H
O
O
N
NH
N
O
3ji 83%
R1=H
R2=CH3
R1=CH3 R2=CH3
3ab 81%
3fb 86c
3am 82%
%
N
H
N
O
Cl
H
N
N
O
H
N
N
O
3fi 63%
3ki 52%
3ii 93%
Table 4 Substrate scope for the synthesis of N-aryl-1,3-benzoxazin-
2-amine derivativesa,b
aReaction conditions: 2-aminophenol (0.20 mmol), Phenyl isothiocyanate (0.30
mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80 °C for 5 h, under
air atmosphere in sealed condition. bYield of isolated products. cThe reaction time
was prolong to 12 h.
NCS
H
NH2
N
N
Cu2O, TBAB
+
OH
n
O
air, H2O, 80 oC, 5h
R2
R2
n=1, 6a
n=2, 8a
7aa, 7ad, 7ae, 9aa
2a, 2d, 2e
In addition, 3-amino-2-naphthol 1k was also compatible to the
optimal conditions. N-Phenylnaphtho[2,3-d]oxazol-2-amine (3ka)
was obtained in 50% isolated yield when 1k were treated with 2a.
When 1-naphthyl isothiocyanate 2i reacts with 1k, the desired N-
(naphthalene-1-yl)naphtho[2,3-d]oxazole-2-amine (3ki) is obtained
in a 52% yield. Phenyl isothiocyanate with electron-donating (p-
OMe) 2g and electron-withdrawing group (p-NO2) 2k were also
tolerant to the reaction with 1k. Obvious electronic effects at the
H
N
H
N
N
O
N
O
7aa 70%
7ad 52%
H
N
H
N
N
N
O
O
F
9aa 20%
7ae 67%
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aReaction conditions: 2-aminobenzyl alcohol (0.20 mmol), Phenyl isothiocyanate
(0.30 mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80°C for 5 h,
under air atmosphere in sealed condition. bYield of isolated products.
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DOI: 10.1039/D0OB01431A
The intermediates of A, B, and F were detected by HPLC-MS
from the control experiments to confirm the role of TBAB and Cu2O
in the present strategy. And the releasing of H2S was confirmed by
the moistened piece of lead acetate paper (See SI).
To test the synthetic potential of this reaction, the detailed
complete synthesis of 3aa at 1 mmol scale was performed (Scheme
1). The 2-aminophenol 1a (4.8 mmol, 523 mg) and phenyl
isothiocyanate 2a (7.2 mmol, 853 μL) reacted smoothly under
optimized conditions, and the corresponding N-phenylbenzoxazole-
2-amine was obtained with a yield of 83% (810.1 mg).
Experimental
NCS
NH2
Cu2O, TBAB
N
O
H
A mixture of 2-aminophenol (0.20 mmol), phenyl isothiocyanate
(0.30 mmol), cuprous oxide (0.20 mmol), TBAB (64.47 mg, 0.20
mmol) and deionized water (1.5 mL) was heated under an air
atmosphere in a screw-cap Schlenk test tube at 80 °C for 5h. After
the reaction was completed, the reaction mixture was cooled to
room temperature then filtered with diatomite. The mixture was
extracted with ethyl acetate (3.0 mL × 3) and the combined organic
phases were dried over anhydrous Na2SO4 and the solvent was
evaporated under vacuum. The residue was purified by column
chromatography to give the corresponding products (ethyl acetate /
petroleum ether = 1: 2-1: 3, 37%-99%).
+
N
H2O, 80 oC, 5h
OH
810.1 mg 83%
4.8 mmol
7.2 mmol
Scheme 1 Gram reaction
In a word, the results illustrated that this is an effective and
facile method for the construction of wide range of
a
heteroaromatic-2-amine motifs since water is considered an
inexpensive and environmentally friendly solvent in green and
sustainable chemistry.
Based on the literatures32 and our above research results, the
mechanism was reported as shown in Scheme 2.
Initially, N-(2-hydroxyphenyl)-N'-(4-fluorophenyl)thiourea
A
were prepared by treatment of 2-aminophenol 1a with 4-
fluorophenylisothiocynate 2e in situ in water. The intermediate A
was then attacked by the nucleophilic bromine of the TBAB to form
the intermediate B, which was stabilized by the
Conclusions
In conclusion, a mild, efficient, economical and environmentally
friendly one-pot approach for 2-Amino benzo[d]oxazole,
benzo[d]thiazole,
tetrabutylammonium cation (TBA+) to facilitate the following
naphtho[2,3-d]oxazole,
and
benzoxazin
[31,
32c-32g]. Subsequently,
derivatives was developed via the oxidative desulfuration and
subsequent dehydrogenative/cyclization of aryl isothiocyanates and
2-aminophenol/2-aminothiophenol or 2-aminobenzyl alcohol in
water. Series of 2-aminophenols (1a–1k) and isothiocyanates (2a–
2k) proceeded well to afford the desired products in moderate to
excellent yields, exhibiting good functional group tolerance. The
electronic and sterical properties have no significant effect on the
reaction. A plausible mechanism was proposed based on literatures.
Further studies on related systems and extension to other
heteroaromatic substrates are currently underway.
intramolecular nucleophilic substitution
nucleophilic substitution takes place by the nucleophilic attack of
the electron-rich oxygen of OH group to C-Br single bond, giving
intermediate C by releasing of anion Br-. Next, the activation of SH
in intermediate C occurred by the interaction of copper (I) species
to give intermediate D. Finally, the one-pot desulfurization and
dehydrogenation of intermediate D afforded the corresponding
product 3ae by elimination of H2S, Cu (II) species and cation
nBu3HN+ (path I).
Another way for the cyclodesulfurization reaction would firstly
involve the direct copper-promoted desulfurization process of
intermediate E33 gained by the interaction of Cu(I) species with the
sulfur atom of intermediate A. Intermediate E converted to the
more reactive imine intermediate F when releasing of H2S. In which
the OH group was activated by tetrabutylammonium cation (TBA+)
to take place the intramolecular nucleophilic substitution,
Conflicts of interest
There are no conflicts of interest to declare.
producing intermediate
G
by leaving of cation TBA+. The
corresponding product 3ae was provided after elimination of Cu(II)
species from G (path II).
Cu(II)
SH
OH
SH
SH
O
Cu2
O
O
N
H
Ar
N
Ar
N
H
N
H
H2O, TBAB
pH=5~6
H
N
Ar
N
Br
H
Br
D
H
C
Pah I
TBA
TBA
B
TBA
Exact Mass for D: [M-Ar-3nBu-H]=300.02
Found : 300.5 (1h); 300.3 (2h)
OH
OH
Exact Mass for B: [ M-TBAB-H]=262.06; Found: 262.4 (1h); 261.5 (2h)
[M-Ar-nBu-Et-H]=402.12; Found: 402.2 (1-3h); 402.3 (4-5h)
S
+
Ar NCS
NH2
N
N
Ar
TBA
H2S,
H
H
A
1a
2e
F
Cu(II)
Cu2
O
Pah II
TBA
H
O
Ar =
H2O, TBAB
pH=5~6
H
TBA
O
Cu(I)
Ar
O
N
O
N
S
NH
F
NH Ar
Cu(II)
N
N
H
NH Ar
F
N
H2S
TBA
Product 3ae
H
Cu
(II)
Cu(II)
E
G
Exact Mass for F: [M-2nBu-H]=420.1
Found : 419.9 (2h); 420.0 (4h)
Scheme 2 A plausible mechanism
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Yella and B. K. Patel. J. Comb. Chem., 2010, 12, 754-763; (c) X.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21102132, 21172200).
View Article Online
Y. Zhang, X. F. Jia, J. J. Wang and X. S. Fan. Green Chem., 2011,
DOI: 10.1039/D0OB01431A
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 10
Table 1 Optimization of reaction conditions.a,b
View Article Online
DOI: 10.1039/D0OB01431A
N C S
OH
N
H
N
catalyst base
H2O T
+
O
NH2
t
2a
3aa
1a
ratio of
1a:2a
yield
(%)b
entrya
copper
additive
atmosphere
T/oC
1
2
3
4
5
6
7
8
--
--
1:1
1:1
1:1
1:1
--
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
open air
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
19
24
51
73
99
83
60
64
9
35
38
70
14
24
46
90
87
82
66
75
92
83
92
81
TBAB
--
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuBr
CuI
CuCl
CuO
CuCl2
CuSO4
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
O2
Ar
9
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
air, sealed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
TBAC
Et3N
t-BuOK
K2CO3
KHCO3
K3PO4
NaOAc
TBAB
TBAB
90
86c; 93d;
96e
26
Cu2O
1:1.5
TBAB
air, sealed
80
aReaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), copper catalyst (0.20 mmol),
additive (0.20 mmol), solvent (1.5 mL) at 80 °C for 5 h, under air atmosphere in
b
c
d
sealed condition. Yield of isolated products. The reaction was finished in 2 h. The
reaction was finished in 3 h. eThe reaction was finished in 6 h.

Page 7 of 10
Organic & Biomolecular Chemistry
View Article Online
Table
2
Substrate scope for the synthesis of N-arylbenzoxazole-2-amine derivativesa,b
DOI: 10.1039/D0OB01431A
R1
NCS
R1
NH2
Cu2O, TBAB
N
H
N
+
OH
R2
air, H2O, 80 oC, 5h
O
R2
2a-2k
1a-1k
3aa-3kk
R1
N
O
R2=H
N
O
H
H
N
R2
N
N
R2
H
R1
N
R2
3fa 94%
R1=CH3 R2=H
R1=CH3 R2=CH3
R1=CH3 R2=F
R1=CH3 R2=Cl
3ba 99%
3bd 99%
3be 90%
3bf 76%
O
3aa 99%
R2=CH3 3ad 90%
R1=CH3 R2=H
R2=F
3ae 94%
R1=CH3 R2=CH3 3fd 95%
R2=OCH3 3ag 84%
R2=CF3 3ah 95%
R2=NO2 3ak 63%
R1=CH3 R2=F
R1=CH3 R2=Cl
3fe 99%
3ff 91%
R1=CH3 R2=OCH3 3bg 77%
R1=F
R2=H
R2=OCH3 3cg 51%
3ca 67%
R1=CH3 R2=OCH3 3fg 89%
R1=F
R1=NO2 R2=H
3ga 84c %
R1=Cl
R1=Br
R1=Br
R1=Br
R1=Br
R2=H
R2=H
R2=CH3
R2=F
3da 75%
3ea 98%
3ed 81%
3ee 66%
3ej 67%
N
H
N
O
R1
N
H
N
O
R2
3ac 90%
R2=I
R1=OCH3 R2=H
3ha 37%
3ia 89%
3ie 85%
N
H
R1=Cl
R1=Cl
R1=Cl
R1=Br
R2=H
R2=F
N
O
N
H
N
O
R2
R2=OCH3 3ig 85%
R2=OCH3 3jg 90%
3ai 65%
R2=H
3ka 58c %
R2=OCH3 3kg 70%
N
R2=NO2
N
3kk 57%
NH
O
R1
Br
R2
3al 63%
N
H
N
H
O
O
N
NH
N
O
3ji 83%
R1=H
R2=CH3
R1=CH3 R2=CH3
3ab 81%
3fb 86c %
3am 82%
N
H
N
O
Cl
H
N
N
O
H
N
N
O
3fi 63%
3ki 52%
3ii 93%
aReaction conditions: 2-aminophenol (0.20 mmol), Phenyl isothiocyanate (0.30
mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80 °C for 5 h, under
air atmosphere in sealed condition. bYield of isolated products. cThe reaction time was
prolong to 12 h.

Organic & Biomolecular Chemistry
Page 8 of 10
View Article Online
DOI: 10.1039/D0OB01431A
Table 3 Substrate scope for the synthesis of N-aryl-1,3-benzothiazole-2-amine
derivativesa,b
NCS
NH2
Cu2O, TBAB
N
H
N
SH
R2
S
air, H2O, 80 oC, 5h
R2
2a-2c
4a
5a-5c
N
S
N
S
H
H
N
N
5aa 99%
5ab 94%
N
S
N
H
N
H
N
S
5ad 61%
5ac 91%
aReaction conditions: 2-aminothiophenol (0.20 mmol), Phenyl isothiocyanate (0.30
mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80 °C for 5 h, under
air atmosphere in sealed condition. bYield of isolated products.
Table 4 Substrate scope for the synthesis of N-aryl-1,3-benzoxazin-2-amine
derivativesa,b
NCS
H
NH2
N
N
Cu2O, TBAB
+
OH
n
O
air, H2O, 80 oC, 5h
R2
R2
n=1, 6a
n=2, 8a
7aa, 7ad, 7ae, 9aa
2a, 2d, 2e
H
H
N
N
N
N
O
O
7aa 70%
7ad 52%
H
N
H
N
N
N
O
O
F
9aa 20%
7ae 67%
aReaction conditions: 2-aminobenzyl alcohol (0.20 mmol), Phenyl isothiocyanate
(0.30 mmol), Cu2O (0.20 mmol), TBAB (0.20 mmol), H2O (1.5 mL) at 80°C for 5 h,
under air atmosphere in sealed condition. bYield of isolated products.

Page 9 of 10
Organic & Biomolecular Chemistry
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NCS
DOI: 10.1039/D0OB01431A
NH2
OH
Cu2O, TBAB
N
O
H
+
N
H2O, 80 oC, 5h
810.1 mg 83%
4.8mmol
7.2mmol
Scheme 1 Gram reaction
Cu(II)
SH
O
OH
N
SH
Cu2O
O
SH
N
H
Ar
N
Ar
N
H
N
H
H2O, TBAB
pH=5~6
H
N
Ar
Br
H
Br
D
H
C
Pah I
TBA
TBA
B
TBA
Exact Mass for D: [M-Ar-3nBu-H]=300.02
Found : 300.5 (1h); 300.3 (2h)
OH
OH
Exact Mass for B: [ M-TBAB-H]=262.06; Found: 262.4 (1h); 261.5 (2h)
[M-Ar-nBu-Et-H]=402.12; Found: 402.2 (1-3h); 402.3 (4-5h)
S
+
Ar NCS
NH2
N
N
Ar
TBA
H
H
A
1a
2e
F
Cu(II)
H2S,
Cu2O
Pah II
TBA
H
O
Ar =
H2O, TBAB
pH=5~6
H
TBA
O
Cu(I)
Ar
O
N
O
N
NH
F
S
NH Ar
Cu(II)
N
N
H
NH Ar
F
N
TBA
H2S
Product 3ae
H
Cu
(II)
Cu(II)
E
G
Exact Mass for F: [M-2nBu-H]=420.1
Found : 419.9 (2h); 420.0 (4h)
Scheme 2 A plausible mechanism

Organic & Biomolecular Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/D0OB01431A
Our work:
R2
NCS
H
R1
R1
N
N
NH2
Cu2O, TBAB
+
R2
80 oC, H2O, 5h
air, sealed
X
n
XH
n=0, X=O, S
n=1, 2, X=O
n
X=O,S
n=0,1, 2
50 examples, up to 99% yield
 good scale-up potential and broad substrate scope
 50 examples, yields up to 99%
 no pre-activated substrate
 efficiency in water media