Synthesis of N-Formyl-2-benzoyl Benzothiazolines, 2-Substituted Benzothiazoles, and Symmetrical Disulfides from N-Phenacylbenzothiazolium Bromides

Article abstract of DOI:10.1021/acs.orglett.9b01990

An unusual aerobic hydrolysis-cascade reaction has been developed with N-phenacylbenzothiazolium bromides by treatment with organic and inorganic base. The corresponding N-formyl-2-benzoyl benzothiazoline and 2-substituted benzothiazole products were obta

Full text of DOI:10.1021/acs.orglett.9b01990

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of N‑Formyl-2-benzoyl Benzothiazolines, 2‑Substituted
Benzothiazoles, and Symmetrical Disulfides from
N‑Phenacylbenzothiazolium Bromides
Subas Chandra Sahoo and Subhas Chandra Pan*
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
S
* Supporting Information
ABSTRACT: An unusual aerobic hydrolysis-cascade reaction has been developed with N-phenacylbenzothiazolium bromides
by treatment with organic and inorganic base. The corresponding N-formyl-2-benzoyl benzothiazoline and 2-substituted
benzothiazole products were obtained in moderate to good yields under mild reaction conditions. Also, symmetrical disulfide
was formed when keto group was replaced with ester. The scopes of the reactions are fairly broad tolerating aryl, heteroaryl, and
alkyl groups.
enzothiazolines are important classes of heterocycles,
which display a wide range of biological and medicinal
activities and are used as antiglutamates, antioxidants,
anticonvulsants, and also as efficient reducing agents1 (Figure
1). Thus, interest in the rapid construction of benzothiazolines
Similarly, benzothiazole motifs are present in a myriad of
natural products and biologically active compounds.4 In
particular, 2-substituted benzothiazoles are utilized as antipar-
asitics, antituberculotics, antitumor agents, and calcium channel
antagonists (Figure 1).5 Thus, a range of synthetic method-
ologies have been developed for the preparation of 2-substituted
benzothiazole derivatives.6 However, little attention was given
for the C2-substituted benzothiazoles with benzylic hydroxyl
group.7 Also, one of the current challenges in synthetic organic
chemistry is to develop efficient, selective, and metal-free
oxidation of organic substrates that utilize dioxygen as the
terminal oxidant.8
B
N-Phenacylbenzothiazolium bromides are useful heterocyclic
ammonium salts, which can generate reactive azo-methine
ylides9 by deprotonation with bases. A range of cycloaddition
reactions have been developed with them by engaging different
olefinic dipolarophiles.10 Also, hydrolysis reactions have been
carried out with strong bases like sodium hydroxide to generate
hemiketalic 1,4-benzothiazines.11 However, to the best of our
knowledge, substituted benzothiazolines have not been
prepared from N-phenacylbenzothiazolium bromides. Herein,
we report unexpected formations of N-formyl-2-benzoyl
benzothiazolines, 2-substituted benzothiazoles, and disulfides
from N-phenacylbenzothiazolium bromides.9
Figure 1. Representative bioactive benzothiazoline, benzothiazoles,
and symmetrical disulfide.
has been observed over the years. Traditionally, benzothiazoline
derivatives are obtained from the condensation of 2-amino-
thiophenols with carbonyl compounds, which requires harsh
conditions.2 Kwon and co-workers developed an alternate
phosphine-triggered general base-catalyzed double-Michael
reaction between 2-aminothiophenols and allenes for the
preparation of C2-functionalized benzothiazolines.3a Never-
theless, diverse methods need to be developed for the
preparation of differently substituted benzothiazolines.
To initiate the investigation, N-phenacylbenzothiazolium
bromide 1a was initially treated with 2 equiv of DABCO in
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
ethanol at room temperature (Table 1). Delightfully, after
stirring for 1 day, (Table 1, entry 1), N-formyl-2-benzoyl
Scheme 1. Scope of 1 with Varied Keto Groups
Table 1. Base Screening and Optimization of Reaction
Conditions
a
b
b
entry
base
solvent
time (h) yield (2a) yield (3a)
1
2
3
4
5
6
7
8
9
DABCO
pyridine
piperidine
DBU
Na2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
DMF
24
24
24
24
36
6
6
6
6
6
25
18
42
68
57
80
80
82
62
90
10
72
48
15
0
5
15
10
10
5
CHCl3
DMSO
10
a
Reaction condition: 0.1 mmol of 1a in 1 mL solvent using 2 equiv of
b
base. Isolated yield after silica gel column chromatography.
benzothiazoline 2a was formed in 25% yield along with
hemiketalic 1,4-benzothiazine 3a (10%). The structure of 2a
was conformed by X-ray crystallography.12 To improve the
yield, different bases were screened. The yield of 2a decreased
with pyridine, but a significant 78% yield was attained for 3a.
Thus, it was expected that 3a was an intermediate for the
formation of 2a. Piperidine provided almost equal amounts of 2a
and 3a. Interestingly, the yield of 2a was improved with DBU.
The reaction also worked with inorganic base such as sodium
carbonate, though moderate yield was detected. Finally, DIPEA
was found to be the best base to provide 80% yield of 2a in 6 h.
To further enhance the yield, different solvents were checked.
Similar yields were observed in CH3CN and DMF, though the
yield decreased in CHCl3. Finally, DMSO turned out to be the
best solvent to deliver product 2a in 90% yield.
a
Reactions were carried out with 0.2 mmol of 1 in 2 mL DMSO using
b
2 equiv of DIPEA at rt for 6−8 h. Yields were determined after
isolation from silica gel column chromatography. Reaction was
carried out with 1 mmol of 1a.
c
obtained in high yields. A 3,4-disubstitution was also tolerated to
deliver product 2l in 78% yield. Benzothiazolium bromide 1m
having 2-naphthyl group also took part in the reaction, and 74%
yield for 2m was detected. Then a reaction was carried out with
2-thienyl substituted salt 1n, and gratifyingly product 2n was
obtained in 84% yield. Moreover, our methodology is also
t
suitable for cinnamyl and butyl substituted benzothiazolium
After N-formyl-2-benzoyl benzothiazoline 2a was obtained in
decent yield, the scope and generality of the methodology were
studied under the optimized conditions. At the beginning, the
aryl group of ketone motif in 1 was varied (Scheme 1). It turned
out that a range of substitutions at the ortho-, meta-, and para-
positions of the aryl group were tolerated. Initially, different
para-substitutions were checked, and good results were attained.
For example, acceptable yield was achieved with benzothiazo-
lium bromide 1b having para-tolyl group. Gratifyingly, an
excellent result was achieved with 4-anisyl group containing salt
1c, and the corresponding product 2c was isolated in 96% yield.
Then different 4-halo substitutions were investigated, and the
products 2d−2f were obtained in varied yields. Though the yield
for product 2d having 4-fluoroaryl group was high, moderate
yield was achieved for product 2f having 4-bromophenyl group.
Benzothiazolium bromide 1g having electron poor nitro group
also participated in the reaction, and moderate yield was
detected. Then biphenyl group containing salt 1h was employed
in the reaction, and product 2h was isolated in 74% yield. The
reaction was also smooth with m-methoxy substituted aryl group
containing salt 1i, and gratifyingly the outcome was good
(Scheme 1). Then ortho-substituted aryl group containing salts
1j and 1k was screened, and the desired products 2j−2k were
bromides 1o and 1p, though slightly lower yields were observed
for the corresponding products 2o and 2p. When the reaction
was carried out in 1 mmol scale, the yield slightly dropped for 2a.
Then we decided to vary the aryl part of 1, and thus, 5-
cholosubstituted N-phenacylbenzothiazolium bromide 1q was
prepared (Scheme 2). Gratifyingly, the reaction progressed well
to provide 2q in moderate yield.
Scheme 2. Employment of 5-Chlorosubstiuted Salt 1b
Then we found a facile formation of 2-substituted
benzothiazole 4a after treatment of N-phenacylbenzothiazolium
bromide 1a with cesium carbonate in ethanol (Scheme 3).
Encouraged by this result, different keto groups containing
benzothiazolium bromides 1 were screened in this condition.
Initially, p-substituted aryl groups containing salts 1 were
B
DOI: 10.1021/acs.orglett.9b01990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of 2-Substituted Benzothiazoles
Scheme 5. Synthetic Transformations
derivatives 7b and 7c were also prepared. Then acid treatment of
2a resulted in the formation of 2-benzoyl benzothiazole 8 in high
yield. Finally, disulfide 5a was refluxed in ethanol with Raney Ni.
Gratifyingly, the desired methyl N-formyl-N-phenylglycinate
(9) was formed in 86% yield.
To understand the mechanism of the reaction, few reactions
were carried out (Scheme 6). After treatment of 1a with DIPEA
a
Reactions were carried out with 0.2 mmol of 1 in 2 mL EtOH using
b
2 equiv of cesium carbonate at rt for 24 h. Yields were determined
after isolation from silica gel column chromatography.
employed in the reaction, and gratifyingly good results were
observed (Scheme 3).
Scheme 6. Control Experiments
For example, product 4b having tolyl group was isolated in
72% yield. Different 4-halo substitutions were also tolerated, and
the corresponding products 4c−4e were obtained in acceptable
yields. The reaction also took place with meta-anisyl containing
salt 1i, and the desired product 4f was attained in 78% yield.
ortho-Anisyl group containing salt 1j also participated in the
reaction to deliver 4g in moderate yield. Then 3,4-dicholosub-
stiuted salt 1l was screened, and a good result was observed for
product 4h. Moreover, heteroaromatic thienyl keto group can
also be incorporated in 1, and the product 4i was isolated in
moderate yield. Interestingly, when tbutyl keto group containing
salt 1p was employed, only formation of benzothiazoline 2p was
observed.
Then we observed formation of symmetrical disulfide 5a after
stirring methylester containing salt 1r with DIPEA in dimethyl
sulfoxide (Scheme 4). Organic disulfides are important
in DMSO−D2O mixture (10:1), product 2a was formed with
60% D in the formamide functionality. Thus, it dictates that
formamide motif could be generated from hydrolysis of 1a with
the moisture present in the solvent. Also, oxygen/air free
reaction was performed in ethanol−water mixture solvent. Here
the major product was 3a. Thus, it is clear that oxygen is helping
for an iminium ion formation, which led to formation of 2a. Also,
reaction of 2a with cesium carbonate delivered 4a in 50% yield.
Thus, it was expected that 4a was formed from 2a.
Scheme 4. Synthesis of Symmetrical Disulfides
A plausible mechanism has been shown in Scheme 7 for the
formations of 2a−5a. It is expected that 10 will first form by
hydrolysis, which under basic condition generates 11. Then an
unusual imine (12) formation takes place under air.18 Finally,
cyclization of 12 delivers 2a. Also, 11 is in equilibrium with 3a,
and interestingly, in our condition, 11 predominates. On cesium
carbonate treatment, 2a is hydrolyzed to form 13. Then 1,2-
hydride shift along with aromatization takes place, and
benzothiazole 4a is formed. Similarly, 1r is converted to 14,
which under basic medium forms disulfide 5a.
structural moieties found in various marine natural products,13
pharmaceuticals,14 materials,15 and polymers.16 The reaction
was also checked with tbutyl ester containing salt 1s, and product
5b was formed in 95% yield.17
The synthetic utility of our method was demonstrated by
performing few useful transformations (Scheme 5). Initially, a
one-pot tandem reaction of 1a was carried out with ammonium
acetate to deliver 6a, which was further treated with Raney Ni to
deliver 4-substituted N-phenylimidazole 7a in good overall
yield. Similar yield was also observed when 2a was treated under
similar reaction conditions. Inspired by this outcome, other
In summary, this report delineates an unusual aerobic
hydrolysis-cascade reaction for the first synthesis of N-formyl-
2-benzoyl benzothiazolines and green approaches for 2-
C
DOI: 10.1021/acs.orglett.9b01990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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substituted benzothiazoles and disulfides. The aerobic for-
mation of iminium ion intermediates as well as disulfides and
1,2-hydride shift for aromatization is rare and will lead further
investigations. Also, synthetic applications such as cascade
formation of N-substituted imidazoles have been demonstrated.
Given the high pharmaceutical importance of benzothiazoline
and benzothiazoles, the newly synthesized products will be
useful for the development of new drugs.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01990.
Experimental procedures and characterization data of all
products (PDF)
(7) (a) Yang, H.; Huo, N.; Yang, P.; Pei, H.; Lv, H.; Zhang, X. Org.
Lett. 2015, 17, 4144. (b) Das, M.; O’Shea, D. F. J. Org. Chem. 2014, 79,
5595.
Accession Codes
CCDC 1921604 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(8) For selected examples, see: (a) Wertz, S.; Studer, A. Adv. Synth.
Catal. 2011, 353, 69. (b) Su, F.; Mathew, S. C.; Lipner, G.; Fu, X.;
Antonietti, M.; Blechert, S.; Wang, X. J. Am. Chem. Soc. 2010, 132,
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Catal. 2005, 347, 1333. (d) Wang, Y.; Li, H.; Yao, J.; Wang, X.;
Antonietti, M. Chem. Sci. 2011, 2, 446. (e) Zheng, G.; Liu, C.; Wang,
Q.; Wang, M.; Yang, G. Adv. Synth. Catal. 2009, 351, 2638. For a review,
see: Chen, B.; Wang, L.; Gao, S. ACS Catal. 2015, 5, 5851.
AUTHOR INFORMATION
■
̈
(9) For selected examples, see: (a) Krohnke, F.; Zecher, W.; et al.
Corresponding Author
*E-mail: span@iitg.ernet.in.
ORCID
Angew. Chem., Int. Ed. Engl. 1962, 1, 626. (b) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
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(e) Eryazici, I.; Moorefield, C. N.; Durmus, S.; Newkone, G. R. J. Org.
Chem. 2006, 71, 1009.
Subhas Chandra Pan: 0000-0002-7581-1831
Notes
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Heterocycles 1981, 15, 807. (b) Tsuge, O.; Kanemasa, S.; Takenaka, S.
Bull. Chem. Soc. Jpn. 1985, 58, 3137. (c) Shen, G.-L.; Sun, J.; Yan, C.-G.
Org. Biomol. Chem. 2015, 13, 10929. (d) Shen, G.; Sun, J.; Yan, C. Chin.
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Chem. 2017, 82, 12763. (f) Zhang, X.; Liu, X.; Zhang, J.; Zhang, D.; Lin,
L.; Feng, X. Org. Chem. Front. 2018, 5, 2126. (g) Jin, G.; Sun, J.; Yang,
R.-Y.; Yan, C.-G. Sci. Rep. 2017, DOI: 10.1038/srep46470.
(11) (a) Peleli, M.; Aggeli, I.-K.; Matralis, A. N.; Kourounakis, A. P.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST SERB, CSIR for the funding. We also thank CIF,
Indian Institute of Technology Guwahati for the instrumental
facility.
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