Aniline ortho C?H Sulfuration/Cyclization with Elemental Sulfur for Efficient Synthesis of 2-Substituted Benzothiazoles under Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.201701560

A three-component synthesis of 2-substituted benzothiazoles from aryl amines, elemental sulfur and styrenes or aryl acetylenes in 1-methylpyrrolidin-2-one (NMP) is described. Two C?S and one C?N bonds were selectively formed in one-pot under metal-free conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201701560

Title: Aniline ortho C-H Sulfuration/Cyclization with Elemental Sulfur for
Efficient Synthesis of 2-Substituted Benzothiazoles under Metal-
Free Conditions
Authors: Guojun Deng, Jingjing Jiang, Guozheng Li, Feng Zhang, and
Hao Xie
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Aniline ortho C-H Sulfuration/Cyclization with Elemental
Sulfur for Efficient Synthesis of 2-Substituted Benzothiazoles
under Metal-Free Conditions
a
a
a,b
a
Jingjing Jiang, Guozheng Li, Feng Zhang, * Hao Xie, Guo-Jun Deng *
a
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally
Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan
4
11105, China. E-mail: gjdeng@xtu.edu.cn; zhangf@iccas.ac.cn.
College of Science, Hunan Agricultural University, Changsha, 410128, China.
b
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 three-component synthesis of 2- addition, it is challenging to remove the trace amount
substituted benzothiazoles from aryl amines, of transition-metals from the sulfur-containing
elemental sulfur and styrenes or aryl acetylenes in 1- heterocycle products due to the strong adsorption
methylpyrrolidin-2-one (NMP) is described. Two C-S between the metal and hetero atoms. Therefore, the
and one C-N bonds were selectively formed in one- development of efficient methods for the synthesis of
pot under metal-free conditions.
sulfur-containing heterocycles from simple and
readily available substrates under metal-free
conditions is highly desirable.
Keywords: 2-substituted benzothiazoles; aromatic
amines; elemental sulfur; metal-free
Benzothiazole derivatives are privileged motif,
which were frequently found in pharmaceuticals and
[7]
many other biologically active products. Moreover,
benzothiazole moieties were also found in many
functional molecules such as ligands for catalytic
The formation of C-S bonds is important because
of their prevalence in many biologically active
[8]
reactions. Over the past few decades, tremendous
progress has been made to synthesize 2-substituted
benzothiazoles, an important class of benzothiazole
[1]
compounds and organic functional materials. The
thiolation (or sulfuration) of arenes usually involves
transition-metal-catalyzed cross-coupling reactions
between active substrates such as organic halides with
thiols or disulfides.[ These methods have the
disadvantage of employing prefunctionalized
substrates and usually require precious metal catalysts
and ligands as well as various additives to get
reasonable reaction yield. While numerous
approaches to C-C or C-N bond formation through
direct C-H functionalization have been developed in
recent years,[ C-S bond formation via C-H
[9]
derivatives.
The condensation reactions of 2-
aminothiphenols with carboxylic acids, aldehydes or
other analogous substrates under oxidative conditions
were used to be the most common method to
2]
[10]
construct various 2-substituted benzothiazoles.
However, 2-aminothiophenols are less readily
available substrates and require multi-step to prepare
[11]
from anilines.
In addition, most of these
transformations involve the use of harsh reaction
conditions. Anilines are one of the most commonly
used synthons in organic synthesis and numerous
anilines with various functional groups are easily and
commercially available. Therefore, the heterocycle
construction based on aniline substrates is a
3]
[4]
functionalization has been much less developed.
Pioneering work by the group of Inamoto in 2008
utilized palladium catalyst to synthesize heterocycles
through intramolecular C-H thiolation.[5] Since then,
various Pd, Cu, Rh, and Ru catalysts have proven to
be successful at promoting this kind of transformation
[
12]
[13]
straightforward approach.
Recently, we
and
[14]
other have reported various methods for C-S bond
construction via direct C-H functionalization in the
absence of transition metal catalyst. These methods
effectively avoid the poisoning of sulfur-containing
compounds to transition-metal catalysts. Cheap and
especially for direct thiolation of electron-rich
heteroarenes.[
4,6]
Although effective methods have
been developed for direct C-S bond formation of
arene C-H bonds, most of them require the use of
transition-metals and/or active thiolation reagents. In
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
readily available elemental sulfur was successfully the reaction was carried out under nitrogen
used as the sulfur source.[
15-16]
However, the synthesis atmosphere (entry 10). Decreasing the reaction
of sulfur-containing heterocycles through direct temperature slightly decreased the reaction yield
sulfuration or thiolation of aniline C-H bond has been (entry 11). When the reaction temperature was
rarely reported.[
17]
As our continuing interest in increased to 150 C, the desired product was observed
o
sulfur-containing heterocycle construction using in 66% yield which is lower to the reaction yield at
o
elemental sulfur as the sulfur source under transition- 140 C (entry 12).
metal-free conditions,[ we herein report a three-
component synthesis of 2-substituted benzothiazoles Table2. Substrate scope with respect to styrenesa
using readily available aromatic amines, sulfur
powder and aryl acetylenes or styrenes as the starting
materials.[
18]
19]
Table1. Optimization of reaction conditionsa
Table3. Substrate scope with respect to aryl acetylenesa
We initiated our study by examining the reaction of
naphthalen-2-amine (1a), styrene (2a), and sulfur
powder in 1-methylpyrrolidin-2-one (NMP) under air
(
sealed tube) (Table 1). To our delight, the desired
product 3a could be obtained in 54% yield in the
absence of any other additives (entry 1). Then several
iodide-containing additives were screened for this
kind of transformation. The addition of catalytic
amount of iodine and KI both resulted in lower yield
(
entries 2 and 3). The reaction yield could be
improved to 67% when 20 mol% of NH I was added
4
as the additive (entry 4). Reactions in other organic
solvents such as DMF, DMA and toluene all resulted
in lower yield (entries 5-8). Interestingly, the reaction
yield could be further improved to 88% when
molecular sieves were added to the reaction mixture
(
entry 9), which may be attributed to its absorbing
ability of small molecule byproducts such as water
and H
S. Similar reaction yield was obtained when styrenes were explored for this kind of reaction (Table
Under the optimized reaction conditions, various
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
2). In general, the reactions between naphthalen-2- We also tried buta-1,3-diyn-1-ylbenzene and isoprene
amine (1a) and the styrene derivatives bearing for this reaction. However, no desired products could
electron-donating groups such as CH
3
and OCH
3
,
be observed in both cases.
halogens such Cl and Br on the aromatic ring all gave
After screened various styrenes and arylacetylenes
the desired products in good yields. When a fluoro for this three-component procedure, we investigated
substituent presented, the desired product 3d was less reactive aniline substrates. However, the desired
obtained in moderate yield. The reaction activity product 5a was obtained in much lower yield when
between styrene (2a) and (E)-(2-bromovinyl)benzene aniline was used as the substrate. We then re-
(
3
2i) is similar, whereby both gave the same product optimized the reaction conditions and we were
a in high yield. The position of substituents on the delighted to find that the reactions could be smoothly
phenyl ring significantly affected the reaction yields, performed by increasing the amount of NH I to 1
and lower yields were obtained when chloro was equiv. and increasing the reaction temperature to 160
4
o
presented at the ortho or meta position (3g and 3h).
Styrenes with strong electron-withdrawing the modified reaction conditions, moderate to good
substituent like NO or CF group were not effective yields were obtained when electron-donating
C without the addition of 4Å MS (Table 4). Under
a
2
3
and only starting materials were observed.
substituted anilines were employed (5b-5l). A mixture
of 5h and 5h’ were obtained in 75% combined yield
when 3-methylaniline was used as the substrate. To
our delight, single product 5i was obtained in 82%
yield when a bulky substituent was presented at the
meta position of aniline substrate. Various di-methyl-
substituted anilines also worked well under the given
reaction conditions to provide the corresponding
products in good yields (5j-5l). The position of
substituents did not significant affect the reaction
yields.
Table 4. Substrate scope with respect to aromatic aminesa
Table 5. Substrate scope with respect to 2-
acylbenzothiazole formationa
Furthermore, we examined the reactions between
naphthalen-2-amine and various arylacetylenes (Table
3). A series of para-substituted phenylacetylenes
smoothly reacted with 1a and sulfur powder to give
the desired products in moderate to good yields (3a-
3f). High yields were obtained when 4-pentyl-2-
ethynylbenzene (4e) and 4-methoxy-2-
ethynylbenzene (4f) were used as the substrates (3k
and 3c). Functional groups such as fluoro, chloro and
bromo were well tolerated under the given reaction
conditions (3d-3f). High yield was obtained when a
chloro group was located at the ortho position of
phenylacetylene (3g). Unfortunately, alkyl-substituted
alkenes and alkynes, such as oct-1-ene and oct-1-yne
were not effective substrate for this kind of
transformation and no desired products could be
observed while the starting materials were recovered.
After we established the 2-alkylbenzothiazole
synthesis under transition-metal-free conditions, we
turned our attention to 2-acylbenzothiazole formation
from styrene (2a), aniline (1b) and elemental sulfur
via a "one-pot, two-step" process (Table 5). After
systematic optimization of the reaction conditions of
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
the second step, we got the optimized conditions for group. These experimental results further demonstrate
-acylbenzothiazole: styrene reacted with aniline and that the thioamide is the reaction intermediate of this
2
o
elemental sulfur at 160 C for 44 h using NH
4
I as the reaction.
additive and then H /DMSO were added to the
O
2 2
reaction and the resulted mixture was further stirred
under oxygen for 24 h. For the model reaction, 6a was
isolated in 60% yield. Various 4-substituented
anilines smoothly reacted with 2a and elemental
sulfur to give the corresponding products in good
yields (6b-6d). Poly-substituted anilines also could be
used as substrates for this kind of transformation to
give the corresponding products in good yields (6e-
6g).
Scheme 2. Possible reaction mechanism.
On the basis of experimental observations and
[20]
previous reports, a possible reaction mechanism is
proposed (Scheme 2). The reaction of aniline (1b)
with elemental sulfur generates an intermediate A.
The addition of A with unsaturated hydrocarbons
[15a-c]
affords intermediate B,
which further couples
aniline to give intermediate C. Subsequently, S-S
bond cleavage of C occurs to release D and thioamide
E. Oxidative cyclization of E affords the final product
5
a, which proceed probably on the assistance of
[21,22]
iodine salt.
In the oxidative step, we suspect the
combination of sulfur and oxygen play a role of
oxidant in current system, although sulfur could be
[23]
the sole oxidant in the absence of oxygen.
In summary, we have developed a novel approach
for the synthesis of 2-substituted benzothiazoles from
aromatic amines, sulfur powder and aryl acetylenes or
Scheme 1. Control Experiments.
For the mechanistic studies of this transformation, a styrenes under metal-free conditions. The C-S bond
series of control experiments were conducted. The formation was realized via direct sulfuration of
addition of a scavenger into the reaction system such aromatic amine C-H bond. Elemental sulfur was used
as butylated hydroxytoluene (BHT) did not inhibited as the sulfur source as well as efficient oxidant. The
the reaction under the standard conditions (Scheme addition of NH
4
I could significantly improve the
1
a). This means the reaction probably proceeds reaction yield. This method affords a simple approach
through a non-radical pathway. When the reaction for 2-substituted benzothiazoles from readily
was stopped within 1 h and 5 h, the desired product available starting materials. The detailed mechanism
was observed in both cases, combined with a certain and the further synthetic applications of this reaction
amount of thioamide. Furthermore, similar results are in progress in our laboratory.
were given when phenylacetylene 4a was used
instead of styrene (Scheme 1b). Then we found that
N,2-diphenylethanethioamide (E) could convert into
the desired product 5a in 88% yield (Scheme 1c).
Experimental Section
General procedure for2-substituted benzothiazoles
When 2,4,6-trimethylaniline (1m) reacted with 2a or
4
a under the standard reaction conditions, a thioamide
Naphthalen-2-amine (1a, 72
phenylethylene (2a, 24 μL, 0.2 mmol), sulfur (25.6 mg, 0.8
mmol), NH I (6 mg, 20 mol%), 4Å MS (100 mg), N-
mg, 0.5
mmol),
intermediate E1 was obtained in 84% and 75% yield,
respectively (Scheme 1d). This intermediate could not
4
further convert into the final product since both ortho methyl-2-pyrrolidone (NMP, 0.6 mL) were added to a 10
positions of the amine group were occupied by methyl mL oven-dried reaction vessel. The sealed reaction vessel
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
o
was stirred at 140 C for 12 h. After cooling to room [6] For selected examples on metal-catalyzed C-S bond
temperature, the reaction was diluted with ethyl acetate (5
mL) and washed with saturated sodium chloride solution.
The organic layer was separated and the aqueous layer was
extracted with ethyl acetate for three times. The residue
was purified by column chromatography on silica gel
formation based on C-H functionalization, see: a) S.
Vásquez-Céspdes, A. Ferry, L. Candish, F. Glorius,
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(
petroleum ether/ethyl acetate = 40:1) to yield the desired
product 3a as yellow solid (49 mg, 88% yield), mp 89-90
o
1
C. H NMR (400 MHz, CDCl
3
) δ 8.03 (d, J = 8.8 Hz, 1H),
7
4
.95 – 7.82 (m, 3H), 7.55 – 7.48 (m, 2H), 7.43 – 7.35 (m,
1
3
H), 7.34 – 7.28 (m, 1H), 4.52 (s, 2H); C NMR (100
) δ 170.3, 151.2, 137.4, 132.7, 130.8, 129.2,
28.9, 128.1, 127.4, 127.0, 126.9, 125.8, 125.0, 121.4, 77.3,
7.0, 76.7, 40.6; HRMS (ESI) m/z calcd. for C18
MHz, CDCl
1
7
3
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Acknowledgements
This work was supported by the National Natural
Science Foundation of China (21572194, 21502160,
2
1372187), the Collaborative Innovation Center of
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6
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Advanced Synthesis & Catalysis
10.1002/adsc.201701560
COMMUNICATION
Aniline ortho C-H Sulfuration/Cyclization with
Elemental Sulfur for Efficient Synthesis of 2-
Substituted Benzothiazoles under Metal-Free
Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Jingjing Jiang, Guozheng Li, Feng Zhang,*
Hao Xie, Guo-Jun Deng*
7
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