A novel self-sequence reaction network involving a set of six reactions in one pot: The synthesis of substituted benzothiazoles from aromatic ketones and anilines

Article abstract of DOI:10.1021/ol400029t

Employing simple and readily available aromatic ketones and anilines as starting materials resulted in the construction of 2-acylbenzothiazoles via a novel self-sequence reaction network, which assembles six reactions in one pot. The reaction network not only supplied a novel method for constructing complex molecules but also provided a typical example for logical self-organization synthesis.

Full text of DOI:10.1021/ol400029t

ORGANIC
LETTERS
2013
Vol. 15, No. 4
890–893
A Novel Self-Sequence Reaction
Network Involving a Set of Six Reactions
in One Pot: The Synthesis of Substituted
Benzothiazoles from Aromatic Ketones
and Anilines
Wei-Jian Xue, Ya-Qiong Guo, Fang-Fang Gao, Hong-Zheng Li, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received January 4, 2013
ABSTRACT
Employing simple and readily available aromatic ketones and anilines as starting materials resulted in the construction of 2-acylbenzothiazoles
via a novel self-sequence reaction network, which assembles six reactions in one pot. The reaction network not only supplied a novel method for
constructing complex molecules but also provided a typical example for logical self-organization synthesis.
The self-organization behavior of molecules is a promi-
nent research topic that has received much attention from
scientists.1 Considering a set of chemical reactions which
act on a finite number of molecules in a well-stirred
solution, the reaction network is not only a useful vehicle
for investigating the self-organization behavior of mole-
cules to imitate biological systems but also an efficient
method for the direct construction of complex compounds
from simple molecules.2 As a result, organic synthesis is now
evolving away from the manipulation of sets of individual
reactions and toward the description and manipulation of
systems of reactions.3 The domino sequence is believed
to incorporate a linear domino sequence (Scheme 1A)3
and multipathway sequence: self-sorting domino se-
quence (Scheme 1B)4a and self-labor domino sequence
(Scheme 1C),4b etc. However, the convergent integration
of two self-labor sequences with a linear domino sequence
can be a long-range complex reaction system, which will
result in a multipathway reaction network (Scheme 1D),
providing a more efficient tool for constructing complex
molecules. In this paper, we report a strategy for the
synthesis of substituted benzothiazoles via assembling six
reactions in one pot.
(1) For selected examples, see: (a) Rosen, B. M.; Wilson, C. J.; Wilson,
D. A.; Peterca, M.; Imam, M. R.; Percec, V. Chem. Rev. 2009, 109, 6275. (b)
Camazine, S.; Deneubourg, J. L.; Franks, N. R.; Sneyd, J.; Theraulza, G.;
Bonabeau, E. Self-Organization in Biological Systems; Princeton University
Press: 2003. (c) Vaidya, N.; Manapat, M. L.; Chen, I. A.; Brunet, R. X.; Hayden,
€
E. J.; Lehman, N. Nature 2012,491, 72. (d) Schmidt-Mende, L.; Fechtenkotter,
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Org. Lett. 2006, 8, 2245. (b) Xue, W. J.; Li, Q.; Zhu, Y. P.; Wang, J. G.;
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2009, 52, 1428. (b) Yoshino, K.; Kohno, T.; Uno, T.; Morita, T.;
Tsukamoto, G. J. Med. Chem. 1986, 29, 820.
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Y.; Pu, X. Dalton Trans. 2011, 40, 7153. (b) Raposo, M. M. M.; Castro,
M. C. R.; Belsley, M.; Fonseca, A. M. C. Dyes Pigm. 2011, 91, 454.
(2) For selected examples, see: (a) Whitesides, G. M.; Ismagilov,
R. F. Science 1999, 284, 89. (b) Gerdts, C. J.; Sharoyan, D. E.; Ismagilov,
R. F. J. Am. Chem. Soc. 2004, 126, 6327. (c) Ganem, B. Acc. Chem. Res.
2009, 42, 463.
(3) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Zhu, J. P.;
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Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
(c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
r
10.1021/ol400029t
Published on Web 01/31/2013
2013 American Chemical Society

in a suitable condition through self-sequenced synthesis
from readily available starting materials assembling six
reactions in one pot.
Scheme 1. Integration of the Domino Reactions Strategy
To test our hypothesis, acetophenone (1a) and 4-meth-
oxyaniline (2b) were used as starting compounds to probe
the favorable conditions. We found that the target mole-
cule (4ab) could be obtained in good yield under the
conditions of 1 equiv of 1a, 1.1 equiv of 2b, 2 equiv of
NaHS nH2O, 2.5 equiv of iodine, 1 equiv of CuO, 0.5
equiv of Cs2CO3, and 0.25 equiv of 1,10-phenanthroline in
3
˚
the presence of a 4 A molecule sieve in DMSO at 120 °C for
24 h (see Supporting Information).
Based on the successful synthesis of the benzothiazole
4ab from 4-methoxyaniline 2b, the optimized conditions
were applied to a range of other starting materials. As
shown in Scheme 3, generally moderate yields were obtained
using aromatic ketones with a substituent (Scheme 3, 4aa to
4na). When anilines with an electron-donating substituent
in the para-position were used as substrates, the corre-
spondingproducts wereobtainedingood yields(Scheme 3,
4ab, 4ac, and 4bc). However, the use of anilines with an
electron-withdrawing substituent in the para-position
lead to the corresponding products being isolated in low
yields or no yield (Scheme 3, 4ad to 4ag). It was established
that 2-iodoaniline derivatives could not be obtained in
good yields with an electron-withdrawing substituent in
the para-position (Scheme 3, 4ae to 4ag). On the other
hand, an electron-donating substituent in the para-position
lead to 2-iodoaniline derivatives being generated in good
yields (Scheme 3, 4ab, 4ac).
Since benzothiazole is a common building block in bio-
logical compounds5 and functional molecules,6 an increas-
ing number of studies have been dedicated toward its
synthesis. Reported methodshavethus far mainly included
the directed synthesis7 and linear domino reaction syn-
thesis8 of benzothiazole. Herein, two self-labor sequences
and a linear domino reaction were bridged to construct
benzothiazole via the formation of two CÀS bonds and
one CÀN bond in one pot.
According to previous literatures, aniline can undergo
iodidation to afford 2-iodoaniline (Scheme 2A),9 aceto-
phenone can be sequentially converted to phenylglyoxal
(Scheme 2B),3 and 2-iodoaniline can react with benzalde-
hyde to generate benzothiazole (Scheme 2C).8d On the
basis of retrosynthetic analysis, it is suggested that the
benzothiazole can be obtained in a novel logical route
(Scheme 2D): convergent intergration of two self-labor
sequences can be bridged together with a linear domino
reaction. We wished that benzothiazole would be generated
To verify that the theoretical model was consistent with
the reaction mechanism, several control experiments were
performed. When 2-iodoaniline was treated with NaHS n-
3
H2O in the presence of CuI, aminothiophenol could not be
found in the reaction mixture (Scheme 4).8d This indicated
that the CÀS bond of 2-aminobenzenethiol could not form
under these conditions.
To determine the roles of copper salts in the cyclization
reaction, the reactions of phenylglyoxal with 2-iodoaniline
and NaHS nH2O were carried out under a variety of condi-
tions. The product was not obtained in the absence of CuO
and CuI (Scheme 5A). However, when CuI was added to the
reaction, the product was formed in 70% yield (Scheme 5B).
Scheme 2. Integration of Reactions
3
(7) For selected examples, see: (a) Joyce, L. L.; Evindar, G.; Batey,
R. A. Chem. Commun. 2004, 446. (b) Evindar, G.; Batey, R. A. J. Org.
Chem. 2006, 71, 1802. (c) Saha, P.; Ramana, T.; Purkati, N.; Ali, M. A.;
Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (d) Blacker,
A. J.; Marsden, S. P.; Williams, J. M. J. Org. Lett. 2009, 11, 2039. (e)
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Y.; Li, P. X. Org. Lett. 2012, 14, 98. (g) Inamoto, K.; Hasegawa, C.;
Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147.
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Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222. (b)
Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835. (c)
Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao, Q. H.; Wu,
A. X. Chem. Commun. 2012, 48, 9086. (d) Park, N.; Heo, Y.; Kumar,
M. R.; Kim, Y.; Song, K. H.; Lee, S. Eur. J. Org. Chem. 2012, 27, 1984.
(e) Ding, Q. P.; Huang, X. G.; Wu, J. J. Comb. Chem. 2009, 11, 1047. (f)
Wang, R.; Chen, Z.; Yue, L.; Pan, W.; Zhao, J. J. Tetrahedron Lett. 2012,
53, 4529. (g) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.;
Saidi, O.; Williams, J. M. Org. Lett. 2009, 11, 2039. (h) Sahoo, S. K.;
Banerjee, A.; Chakraborty, S.; Patel, B. K. ACS Catal. 2012, 2, 544. (i)
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Org. Lett., Vol. 15, No. 4, 2013
891

In order to prove the reaction mechanism, possible
intermediates were isolated and purified to participate in
reactions as starting materials (Scheme 6). 5a was observed
Scheme 3. Synthesis of Benzothiazoles 4 from Aniline 2a
to react with 3a and NaHS nH2O to generate 4aa in good
3
yield in the presence of CuI, Cs2CO3, and 1,10-phen
(Scheme 6A). The target molecule 4aa could be obtained
from 5a reacting with 2a (Scheme 6B). However, 4aa did
not form when 6a reacted with 2a (Scheme 6C). This
indicated that the intermediate from 6a reacting with 2a
could not be iodinated to form the target molecule 4aa. It
was subsequently found that benzothiazoles 4 could be
obtained from the reaction of aromatic ketones 1 with
2-iodoanilines 3 (Scheme 6D). Capable of assembling five
reactions in one pot, this was a novel linear domino
reaction: a new method for synthesizing benzothiazoles.
All benzothiazole derivates can be obtained in moderate to
good yields through this method (19 examples in the
Supporting Information).
Scheme 6. Reactions between Possible Intermediates
a Reaction was performed with 0.5 mmol of 1, 0.55 mmol of 2, 1 mmol
of NaHS nH2O, 1.25 mmol of I2, and 0.5 mmol of CuO in the presence
3
˚
of a 4 A molecule sieve, Cs2CO3, and 1,10-phenanthroline in 3 mL of
DMSO at 120 °C for 24 h. Isolated yields provided.
Scheme 4. Attempted Reaction between 3a and NaHS nH2O
3
Finally, in order to investigate the detailed reaction
process, GC-MS was used to detect the proposed inter-
mediates for this reaction. We could not detect any signals
of 7aa, when 6a reacted with 3a in DMSO. This result
implied that 7aa could be oxidized by DMSO. CHCl3
was used as solvent, and 7aa was subsequently detected
in moderate yield (Scheme 7A). Due to the instablility of
7aa, the crude intermediate 7aa was used as a substrate
to synthesize 4aa. Fortunately, in addition to the target
molecule 4aa, 8aa was also be found in the mixture
(Scheme 7B). When 1a and 2c were used as substrates,
3c and 8ac were detected. These results indicated that
compounds 3, 7, and 8 were important intermediates
(Scheme 7C). These experiments implied that the assem-
bling procedure of three sequences in one pot was achieved
via the self-organization behavior of the molecule.
Scheme 5. Effect of Copper in the Reaction
Yet, when CuI was replaced by CuO, the product was not
found (Scheme 5C). These results clearly demonstrated
that CuI could catalyze the reaction of phenylglyoxal with
Based on the above experiments, we can confirm that the
reaction mechanism was consistent with our theoretical
model. In addition, the possible mechanism for this reac-
tion can be illustrated with the example of acetophenone
2-iodoaniline and NaHS nH2O where CuO could not.
3
892
Org. Lett., Vol. 15, No. 4, 2013

Scheme 7. Detected Reactions by GC-MS
Scheme 8. Plausible Mechanism of the Present Reaction
(1a), 4-methoxyaniline (2b), and NaHS nH2O (as shown
3
in Scheme 8). 2b could be iodinated to 3b, while acetophe-
none (1a) could be sequentially converted to phenylgly
oxal (6a) at the same time. Then 3b could condense with
phenylglyoxal (6a) to form 7ab. 7ab could react with
enrich the reaction network system. Further investigations
into the design of new reaction networks and their sub-
sequent applications will be reported in due course.
NaHS nH2O to generate intermediate 8ab. Based on the
literature,7b we know that the byproduct CuI could cata-
lyze 8ab to produce the target molecular 4ab.
3
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Grants 21032001 and 21272085)
and PCSIRT (No. IRT0953).
In conclusion, we have achieved the convergent inter-
gration of two self-labor sequences with a linear domino
reaction. This novelstrategycould be used for constructing
benzothiazoles via assembling six reactions in one pot. To
thebestofourknowledge, thistransformation hasnotonly
supplied a novel method for directly synthesizing ben-
zothiazoles from readily available aromatic ketones and
anilines but has also provided a typical example for self-
organization logical synthesis of organic compounds to
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
893