Domino Synthesis of 2-Substituted Benzothiazoles by Base-Promoted Intramolecular C-S Bond Formation

Article abstract of DOI:10.1021/acs.orglett.9b02855

A new, transition-metal-free, domino synthesis of 2-substituted benzothiazoles has been developed, involving base-promoted one-pot addition of active methylene compounds to o-iodoarylisothioacyanates and subsequent intramolecular C-S bond formation of the

Full text of DOI:10.1021/acs.orglett.9b02855

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Domino Synthesis of 2‑Substituted Benzothiazoles by Base-
Promoted Intramolecular C−S Bond Formation
Yogendra Kumar and Hiriyakkanavar Ila*
New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India
S
* Supporting Information
ABSTRACT: A new, transition-metal-free, domino synthesis of 2-substituted
benzothiazoles has been developed, involving base-promoted one-pot addition
of active methylene compounds to o-iodoarylisothioacyanates and subsequent
intramolecular C−S bond formation of the resulting thioamidate anion. The
reaction proceeds at room temperature within 1−3 h, affording diversely
substituted benzothiazoles in high yields. A possible radical intermediate pathway, via an SRN1 mechanism, has been proposed
for intramolecular C−S bond formation.
2-Substituted benzothiazoles make up an important class of
nitrogen- and sulfur-containing heterocycles, present in several
important natural products and synthetic compounds,
displaying a broad range of biological activities,1,2 such as
anticancer, anti-Alzheimer’s, antibacterial, and antimicrobial
activities,2 and have also found application in material science.3
Therefore, the development of new, efficient synthetic
methods for diversely functionalized benzothiazoles has
attracted much attention among synthetic and medicinal
chemists.
e).2f,8 Recently, 2-substituted benzothiazoles have also been
obtained from thiobenzanilides via photoredox single-electron
transfer (SET) pathway employing Ru(I)polypyridine com-
plexes (Scheme 1, f).9 However, the use of toxic and expansive
transition-metal catalysts/ligands, prefunctionalization of start-
ing materials, harsh reaction conditions, and somewhat limited
substrate scope diminishes the attractiveness of these methods.
To overcome these shortcomings, much attention has been
paid to the development of transition-metal-free protocols, and
in recent years, “transition-metal-free cross-coupling processes”
for the formation of C−C, C−N, C−O, and C−S bonds have
attracted considerable interest among synthetic organic
chemists.10 Several research groups have reported significant
contribution in this field, including transition-metal-free C−H
arylations, for the construction of biphenyl frameworks.11
Bolm and co-workers, in their pioneering work, first reported a
detailed study of intermolecular cross-coupling reactions
between aryl halides and various sulfur-, oxygen-, and
nitrogen-based nucleophiles (N-, O-, and S-arylation, respec-
tively) in the presence of KOH/DMSO as “superbase”
medium12,13 under TM-free conditions. In particular, these
workers and others14,15 have also developed base-promoted
transition-metal-free intramolecular C−heteroatom bond
formation reactions, which showed great potential for the
synthesis of heterocyclic compounds such as 2-oxobenzimida-
zoles,14a phenoxazines,14b indazoles,14a,15a benzimidazo-
les,14d,15d oxindoles,14e indoles,15b and benzofurans.15c Some
of these transition-metal-free coupling reactions are shown to
proceed by direct nucleophilic aromatic substitution (SNAr
reaction) or via a benzyne mechanism, whereas others were
proposed to occur via single-electron reduction of aryl halides,
involving radical or radical ion species (SRN1 reactions),10,11
sometimes also termed “electron-catalyzed reactions”.11d,12f,15b
During the course of our ongoing work on the synthesis of
five- and six-membered heterocycles and their benzo-fused
Among some of the oldest methods, oxidative cyclization of
thiobenzanilides4 is the most widely used route for the
synthesis of benzothiazoles (Scheme 1, a). The other common
Scheme 1. Methods for the Synthesis of Benzothiazoles
methods involve oxidative condensation of 2-aminothiophe-
nols with aldehydes or carboxylic acids (Scheme 1, b).5 Recent
advances in carbon−heteroatom bond formation have led to
the development of several new methods for the synthesis of
benzothiazoles and their analogues, involving transition-metal-
catalyzed intramolecular C−S bond formation of o-halothio-
benzanilides (Scheme 1, c).2a,e,6 Similar transformations have
also been achieved in few cases, through base-promoted
intramolecular arylation reactions of these substrates, at higher
temperatures (SNAr reactions) (Scheme 1, d).7 Alternatively,
benzothiazoles have also been prepared directly through
transition-metal-catalyzed C−H functionalization of readily
available thiobenzanilides or thiourea derivatives (Scheme 1,
Received: August 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02855
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
analogues,16 employing organosulfur intermediates, we now
report a facile transition-metal-free protocol for the synthesis of
2-substituted benzothiazoles via base-promoted tandem
addition−intramolecular cyclization of o-iodoarylisothiocya-
nates with various active methylene compounds in DMSO.
Substituted benzothiazoles bearing an active methylene
group at position 2 have not been much explored in the
literature.17 A few of these compounds have found applications
in medicinal chemistry as well as in material science. Thus, 2-
[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamides
and their salts are shown to display “Aurora Kinase,
VEGFR218a and C-jun-N-terminal (JNK) kinase18b inhibitor”
activity (A and B) and are useful in the treatment of cancer
(Figure 1). Similarly, few benzothiazolo-fused 5-oxo-6-
by deprotonation of active methylene compounds 2 will add to
2-halophenylisothiocyanate 1, yielding a stabilized thioamidate
anion 4, which would undergo copper-catalyzed intramolecular
C−S bond formation, yielding the desired 2-substituted
benzothiazoles 3. Alternatively, we also envisioned that
thioamidate anion 4 could also undergo intramolecular C−S
bond formation, leading to 2-substituted benzothiazoles 3
under transition-metal-free conditions via either nucleophilic
aromatic substitution (SNAr) or through a radical pathway
mechanism (Scheme 2).
We therefore initiated our studies by reacting o-iodopheny-
lisothiocyanate 1a with acetylacetone 2a as model substrates
for the optimization of reaction conditions, for the synthesis of
[2-benzothiazol-2(3H)-ylidene]acetylacetone 3a under copper
catalysis (Table 1). Thus, when 1a and 2a were reacted in the
presence of NaH (2 equiv) as the base, CuI (10 mol %) as the
catalyst, and proline as the ligand (20 mol %) in DMF, at rt for
5 h, 3a was obtained in only 47% yield (Table 1, entry 1). At
higher temperatures, the yield of 3a was increased to 75%
(Table 1, entry 2). Similarly, changing the ligand from proline
to 1,10-phenanthroline resulted in higher yields of 3a (Table 1,
entry 3). However, a dramatic increase in the yield of 3a was
observed, when the reaction was conducted in the presence of
CuI, in DMSO as a solvent, even at rt (Table 1, entry 4). The
reaction also proceeded smoothly in DMSO under ligand-free
conditions, furnishing 3a in a comparable yield (Table 1, entry
5). We therefore started wondering whether copper catalysis
was necessary for this cyclization, and indeed, to our delight,
when 1a and 2a were reacted in the absence of CuI under
identical conditions in DMSO, starting materials were
consumed within 1 h at rt and 3a was isolated in 92% yield
(Table 1, entry 6).
With these unexpected results in hand, we further examined
the effect of various solvents and bases on the yield of 3a under
transition-metal-free reaction conditions (Table S1). Thus, the
reaction of 1a and 2a was found to be slower at rt in the
presence of bases like t-BuOK, KOH, K2CO3, and Cs2CO3, in
DMSO as the solvent, whereas reasonably good yields of 3a
were obtained at higher temperatures after 5−12 h (Table S1,
entries 2−6). However, poor yields of 3a were obtained by
employing other solvents (DMF, toluene, THF, and CH3CN)
even at higher temperatures (Table S1, entries 7−10,
respectively), whereas use of 1 equiv of NaH resulted in a
diminished yield of 3a (Table S1, entry 11). We therefore
employed NaH (2 equiv) as a base in DMSO at rt as optimal
reaction conditions for further studies (Table S1, entry 1).
We next explored the scope of this novel transition-metal-
free synthesis for other 2-substituted benzothiazoles 3 by
Figure 1. Biologically important 2-substituted benzothiazoles.
carboxyquinoline and naphthyridine scaffolds (C) also exhibit
antibacterial properties.19 Recently, a few of the benzothia-
zole−pyrimidine bidentate ligand-based boron difluoride20a
and BODIPY complexes20b (D) have been synthesized, which
are found to be selective and sensitive fluorescent sensors for
cysteine (Figure 1). Some of these multifunctional benzothia-
zoles have also been employed as synthetic intermediates for
fused heterocycles.17,19b,21 These compounds have been
synthesized in the literature by nucleophilic displacement of
the corresponding polarized ketene dithioacetals by 2-amino-
thiophenols.17,18,19b
Our proposed synthesis of benzothiazoles 3 is shown in
Scheme 2. Thus, we anticipated that the carbanion generated
Scheme 2. Proposed Synthesis of 2-Substituted
Benzothiazoles
Table 1. Optimization of Reaction Conditions for the Synthesis of Benzothiazole 3a
a
entry
catalyst (10 mol %)
ligand (20 mol %)
base (2 equiv)
solvent
temp (°C)
time (h)
% yield (3a)
1
2
3
4
5
6
Cul
Cul
Cul
Cul
Cul
−
proline
proline
1,10-phen
proline
−
NaH
NaH
NaH
NaH
NaH
NaH
DMF
DMF
DMF
DMSO
DMSO
DMSO
rt
5
5
5
5
4
1
47
75
81
91
90
92
60
60
rt
rt
rt
−
a
Yields of pure isolated product.
B
DOI: 10.1021/acs.orglett.9b02855
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Organic Letters
Letter
reacting various active methylene compounds with o-
iodoarylisothiocyanates 1 in DMSO under optimized reaction
conditions (Scheme 3). Thus, acyclic active methylene
compounds such as 4-chlorobenzoylacetonitrile 2m, phenyl-
acetonitriles 2n and 2o, and 2-pyridylacetonitrile 2p also
underwent smooth tandem addition−cyclization with o-
iodophenylisothiocyanate 1a under identical conditions,
affording various 2-functionalized benzothiazoles 3m−p in
high yields (Scheme 3). The use of less acidic ketones such as
4-chloroacetophenone 2q, or 4-acetylpyridine 2r, also did not
affect the yields of the corresponding product 3q or 3r,
respectively, each of which was obtained in overall high yields.
We next investigated the effect of substituents on o-
iodoarylisothiocyanates 1b−d bearing both electron-with-
drawing and electron-donating substituents on the aryl ring
(Scheme 3). Thus, the reaction of isothiocyanates 1b and 1c
bearing either 4-chloro or 4-(trifluoromethyl) groups with
acetylacetone or other active methylene compounds proceeded
smoothly under identical conditions within 1 h, furnishing the
corresponding [2-benzothiazol-2(3H)-ylidene]carbonyl/nitrile
compounds 3s−x in high yields (Scheme 3). On the other
hand, the corresponding 4,5-(dimethoxy)-2-iodophenylisothio-
cyanate 1d bearing electron-donating groups afforded cyclized
benzothiazoles 3y and 3z in decreased yields upon reaction
with 2a and 2i, respectively, although the reaction was
complete within 3 h (Scheme 3).
Scheme 3. Substrate Scope for the Synthesis of 2-
a
Substituted Benzothiazoles 3
The reactivity of few o-halophenylisothiocyanates 1e−g
bearing bromine, chlorine, and fluorine, respectively, was also
examined toward acetylacetone, along with few additional
experiments to provide some insight into the mechanism of
this facile transition-metal-free coupling reaction (Table 2 and
Table 2. Base-Mediated Reactions of Various o-
Halophenylisothiocyanates 1a and 1e−g with Acetylacetone
entry
1
X
Y
temp (°C)
time (h)
% yield (3a)
1
2
3
4
5
6
7
8
1a
1e
1e
1f
I
H
H
H
H
H
H
H
I
rt
rt
90
rt
90
rt
1
12
12
12
12
12
12
24
92
−
57
Br
Br
Cl
Cl
F
−
1f
60
30
70
a
1g
1g
1h
Reaction conditions: 1 (1 mmol), 2 (1 mmol), and NaH (2 equiv)
F
H
60
rt
in DMSO under N2 stirred at rt for 1−3 h. Yields of pure isolated
product. The reaction was complete after the mixture had been stirred
at 60 °C for 6 h.
a
−
a
The isolated product was found to be thioamide 5 (Scheme 3).
Scheme 4). Thus, no trace of 3a was observed in the reaction
mixture, when the corresponding o-bromo- and o-chlorophe-
nylisothiocyanates (1e and 1f, respectively) were reacted with
compounds such as dibenzoylmethane, diethylmalonate, ethyl
acetoacetate, ethyl cyanoacetate, and malononitrile 2b−f
reacted efficiently with o-iodophenylisothiocyanate 1a under
optimal conditions, yielding the corresponding 2-substituted
benzothiazoles 3b−f in excellent yields. The reaction was
found to be equally facile with cyclic 1,3-diketones 2g−i,
furnishing the corresponding sterically crowded [2-benzothia-
zol-2(3H)-ylidene]-1,3-diketones 3g−i in nearly quantitative
yields (Scheme 3). Further variation in substrate structures by
employing sterically incumbent cyclic 1,3-dimethyluracil,
thiouracil, and meldrum’s acid 2j−l also did not affect the
yields of benzothiazole products 3j−l, respectively. The
structure of these products was further confirmed by X-ray
crystallographic data of compound 3h (see Figure S1). The
corresponding unsymmetrically substituted active methylene
Scheme 4. Reaction of o-Iodophenylisothiocyanate with
Acetylacetone in the Presence of TEMPO and Air
C
DOI: 10.1021/acs.orglett.9b02855
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Letter
2a at rt under optimized conditions, even after a prolonged
time (Table 2, entries 2 and 4). However, at a higher
temperature of 90 °C, 3a was obtained in 57% and 60% yields
after prolonged heating (Table 2, entries 3 and 5, respectively).
On the other hand, the corresponding o-fluorophenylisothio-
cyanate 1g gave an only 30% yield of benzothiazole 3a at rt
even after 12 h (Table 2, entry 6), whereas at 60 °C, 3a was
obtained in a higher yield (70%) (Table 2, entry 7). The
addition of TEMPO, a common trapping agent for free
radicals, nearly completely inhibited the cyclization (Scheme 4,
eq 1). Similarly, when 1a and 2a were reacted in the absence of
a nitrogen atmosphere in air, product 3a was isolated in only
15% yield (Scheme 4, eq 2). These observations point toward
the involvement of radical intermediates and/or a SET process,
in this transformation. Also, when m-iodophenylisothiocyanate
1h was reacted with acetylacetone 1a under standard reaction
conditions, no trace of benzothiaziole 3a was formed even after
a prolonged time (Table 2, entry 8), thus demonstrating that
the benzyne intermediate is not involved in this cyclization
reaction.
zoles, involving base-mediated tandem addition−intramolecu-
lar cyclization of o-iodoarylisothiocyanates and active methyl-
ene compounds. The key features of the synthesis are that the
reaction proceeds at rt, within 1−3 h, in high yields, in the
absence of any ligand or additive. On the basis of various
studies, a reasonable mechanism involving formation of radical
intermediates (SRN1) has been proposed. To the best of our
knowledge, such a transformation involving intramolecular C−
S bond formation at rt,14c leading to benzothiazoles, under
mild transition-metal-free conditions has not been reported in
the literature.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02855.
Experimental details, table of the optimization of
reaction conditions for the synthesis of 3a (Table S1),
melting points, 1H and 13C NMR spectra, IR spectra for
all products, and analytical data (PDF)
On the basis of the previous reports and our own
observations, we propose a possible radical intermediate
pathway through an SRN1 mechanism for this transition-
metal-free domino synthesis of benzothiazoles 3 (Scheme 5).
Accession Codes
CCDC 1952893 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 emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Proposed Mechanism for Base-Mediated
Formation of Benzothiazole 3a from 1a and 2a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hila@jncasr.ac.in.
ORCID
Hiriyakkanavar Ila: 0000-0002-6971-8374
Notes
Thus, the addition of a carbanion (generated by deprotonation
of 2a) to o-iodophenylisothiocyanate 1a affords, initially,
thioamide intermediate 4A, which is transformed into its
conjugate base 4B, under basic conditions. Anionic inter-
mediate 4B serves as an electron donor, to initiate the radical
process and undergoes intramolecular electron transfer to the
aryl part of 4B, to give radical anion intermediate 6. Finally, the
loss of the iodide ion from intermediate 6 affords diradical
intermediate 7, which undergoes intramolecular radical
combination to furnish product 3a (Scheme 5). Because
only o-iodoarylisothiocyanate derivatives 1a−d cyclized
efficiently to benzothiazoles 2, whereas o-bromo, o-chloro,
and o-fluoro derivatives (1e−g, respectively) were found to be
either completely inert or sluggish under identical conditions
(Table 2, entries 2, 4, and 6, respectively), we consider that an
intramolecular nucleophilic substitution pathway (SNAr) is
unlikely, because the reactivity of o-halophenylisothiocyanates
1a and 1e−g does not follow the expected order of reactivity
(F > Cl > Br > I) for a standard SNAr mechanism. The
decreased yields of benzothiazoles 3y and 3z obtained from
4,5-dimethoxy-2-iodophenylisothiocyanate 1d (Scheme 3)
appear to be due to the destabilization of radical anion
intermediate 6, because of the presence of two electron-
donating methoxy groups.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Council of Scientific and Industrial
Research (CSIR, New Delhi) for CSIR-SRF (to Y.K.),
JNCASR, Bangalore, and a Hindustan Lever Research
Professorship (to H.I.).
DEDICATION
■
This paper is dedicated to Prof. C. N. R. Rao, FRS, on the
occasion of his 85th birthday.
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DOI: 10.1021/acs.orglett.9b02855
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