A facile one pot synthesis of thiazolo[3,2-: A] benzimidazole and pyran fused polyheterocyclic scaffolds

Article abstract of DOI:10.1039/c9ob00300b

An efficient synthesis of dihydro-4H-benzo[4,5]imidazo[2,1-b]pyrano[2,3-d]thiazole by a multicomponent route starting from 2-((1H-benzo[d]imidazol-2-yl)thio)-1-phenylethan-1-one, an aromatic aldehyde and malononitrile is described. This protocol features

Full text of DOI:10.1039/c9ob00300b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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A facile one pot synthesis of thiazolo[3,2-a]benzimidazole and
pyran fused polyheterocyclic scaffold
Arumugam Mariappan,a Kandasamy Rajaguru,a Shanmugam Muthusubramanian,a* and Nattamai
Received 00th January 20xx,
Accepted 00th January 20xx
Bhuvaneshb
DOI: 10.1039/x0xx00000x
An efficient synthesis of dihydro-4H-benzo[4,5]imidazo[2,1- carboxamide (YM-298198) (Fig.1) is reported to be
a
b]pyrano[2,3-d]thiazole by a multicomponent route starting from noncompetitive antagonist of metabotropic glutamate
2-((1H-benzo[d]imidazol-2-yl)thio)-1-phenylethan-1-one, aromatic receptor type-I.10
aldehyde and malononitrile is described. This protocol features
metal free approach with good substrate scope and decent yield.
The heterocyclic skeleton obtained in this study may have
interesting biological properties.
Polyfused heterocyclic systems have played an important role
in the field of organic chemistry owing to their presence in
Fig. 1 Some biologically active derivatives of thiazolo[3,2-a]benzimidazoles.
various bioactive compounds and commercially available
drugs.1 The complexity and the highly pronounced biological
Pyrans, in particular poly-functionalized 4H-pyrans, are
important building blocks for several natural and synthetic
and pharmacological activity associated with the polycyclic
systems tempted the chemists to design novel strategies for
heterocyclic compounds with antitumor, antibacterial,
their construction.2 Multicomponent reactions have found to
be the best choice for the synthesis of such polyheterocycles
with different skeletons.3 Benzimidazole fused heterocycles in
general and benzimidazothiazoles in particular are shown to
antiviral, spasmolytic, and antianaphylactic properties.11
Owing to their wide applications, plenty of methods have been
developed for their synthesis.12 Spirothiazolopyrans have been
synthesized from spirothiazolidinones.13 A novel approach for
the synthesis of a pyrazole based trifluoromethyl substituted
fused thiazolopyran scaffold has been claimed by a one-pot
four-component tandem type reaction.14
In the present work, we are describing the synthesis of a
heterocyclic system embedding both the thiazolo[3,2-
a]benzimidazole and dihydro-4H-pyran. To the best of our
knowledge, this is the first report of thiazolobenzimidazole
fused pyran scaffolds from simple starting materials. This fused
system may have improved biological characteristics than that
of the related individual heterocycles. Multicomponent
reactions have been effectively utilized as a tool for the eco-
friendly synthesis of various heterocyclic compounds in our
laboratory.15 In continuation of that, the construction of fused
have wide range of biological activities.4
Thiazolo[3·2-
a]benzimidazole (I) and several of its derivatives were
synthesized by annelation of the thiazole ring to
a
benzimidazole.5 A one-pot process provided an efficient and
successful approach for the synthesis of a new thiazolo[3,2-
a]benzimidazole linked-quinazoline scaffold with good to high
yields.6 2-Mercaptobenzimidazole was used in the synthesis of
several
thiazolo[3,2-a]benzimidazole.7
Thiazolo[3,2-
a]benzimidazoles skeleton can be prepared from
diisothiocyanates.8
[3-(4-Chlorophenyl)-[1,3]thiazolo[3,2-a]benzimidazol-2-yl]
acetic acid (Tilomisole) (WY-18,251) (Fig. 1) has shown anti-
inflammatory and anti-cancer properties.9
6-Amino-N-
cyclohexyl-N,3-dimethylthiazolo[3,2-benzimidazole-2-
heterocyclic
system
dihydro-4H-benzo[4,5]imidazo[2,1-
b]pyrano[2,3-d]thiazole is reported in the present work.
Our investigation started with a mixture of 2-((1H-
a.Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, India.
benzo[d]imidazol-2-yl)thio)-1-phenylethan-1-one
1 (1 mmol),
b.X-ray Diffraction Laboratory, Department of Chemistry, Texas A & M University,
College Station, Texas, TX 77842, USA.
aryl aldehyde
malononitrile
2
3
(1 mmol), sodium hydroxide (1.5 mmol) and
(1 mmol) taken in that order in ethanol, which
E-mail: muthumanian2001@yahoo.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
was stirred at room temperature.
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DOI: 10.1039/C9OB00300B
Scheme 2 Mass fragmentation of 4.
The structure of the product
4
was unambiguously
assigned by spectral and analytical data and that of 4k (Table
2) was confirmed by single-crystal X-ray analysis (Fig.2).17
Table 2 Synthesized compounds 4a- 4s.a
Scheme
d]thiazole.
1 Synthesis of dihydro-4H-benzo[4,5]imidazo[2,1-b]pyrano[2,3-
Normally, the combination of RCOCH2R΄, malanonitrile and
an arylaldehyde in the presence of alcohol leads to pyridine
derivatives.16 But the active methylene system employed in
this case has acidic hydrogen in the benzimidazole ring and
hence we anticipated a different cyclisation.
Table 1 Optimisation of reaction conditions.a
Time
(Mins)
30
50
40
35
55
45
25
30
55
45
20
20
20
Yield (%)b of
Entry
Base
Equiv
Solvent
4a
78
25
40
30
20
15
60
73
35
43
85
83
85
1
2
3
4
5
6
7
8
9
10
11
12
13
NaOH
Piperidine
DBUc
Diethylamine
Na2CO3
K2CO3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
2.1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Water
MeOH
DMF
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
ACN
EtOH
MeOH
EtOH
aReaction conditions: 2-((1H-benzo[d]imidazol-2-yl)thio)-1-phenylethan-1-
one 1 (1 mmol), Aromatic aldehyde 2 (1 mmol,) with base and malononitrile
3 (1.5 mmol) and (1 mmol) in Solvent (5 mL) stirring at rt for 15-60 mins.
aReaction conditions: 2-((1H-benzo[d]imidazol-2-yl)thio)-1-phenylethan-1-
one 1 (1 mmol), Aromatic aldehyde 2 (1 mmol,) with NaOH and
malononitrile 3 (1.5 mmol) and (1 mmol) in EtOH (5 mL) stirring at rt for 15-
60 mins. bIsolated yield by filtration and recrystallization.
bIsolated yield by filtration and recrystallization. CDBU
Diazabicycloundec-7-ene.
=
1,8-
Upon completion of the reaction, the isolated product was
found to be dihydro-4H-benzo[4,5]imidazo[2,1-b]pyrano[2,3-
d]thiazole 4 and not benzimidazothiazepene 4′ (Scheme 1).
The polycyclised product
through retro Diels Alder reaction in the ESI-mass spectrum
4 undergoes easy fragmentation
leaving
the
molecular
ion
associated
(Scheme
with
2,
3-
arylbenzo[4,5]imidazo[2,1-b]thiazole
see
supporting information). Encouraged by this serendipity result,
we optimized the reaction conditions further. Initially the
mixture of 1a (1.0 equiv), stoichiometric amount of 2a (1.0
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equiv) along with sodium hydroxide (1.1 equiv) was added
with malanonitrile in ethanol and stirred at room
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DOI: 10.1039/C9OB00300B
3
temperature (Table 1, entry 1). The reaction got completed in
just 15 minutes. Nitrogen bases such as piperidine, DBU (1,8-
Diazabicycloundec-7-ene) and diethylamine (Table 1, entries 2-
4) and mild inorganic bases such as sodium and potassium
carbonates (Table 1, entries 5-6) were also tested in the place
of sodium hydroxide. Relatively low yield was obtained in
these cases, suggesting that a strong base like sodium
hydroxide is essential for the conversion.
We then attempted to optimize the appropriate solvent for
this transformation. In the course of solvent optimization, it
was noticed that the polar protic solvents (Table 1, entries 1, 7
& 8) are efficient for this transformation than the aprotic polar
solvents (Table 1, entries 9-10). Increasing the equivalency of
base (1.5 equiv) promoted the reaction (Table 1, entries 11-
12), whereas further enhancement in the equivalency of base
(2.1 equiv) had no improvement in the yield of the product
(Table 1, entry 13). With the optimized reaction conditions in
hand, we then examined the substrate scope of this
Scheme 2 Plausible mechanism for the formation of 4.
multicomponent reaction with different arylaldehydes
2 and
various derivatives of to obtain a library of (Table 2). The
1
4
Conclusions
aldehydes with electron-donating groups enhanced the yield,
whereas the electron-withdrawing groups in the aryl ring of
the aldehyde part reduced the yield (Table 2).
We have described an expedient and convergent three-
component domino protocol for the synthesis of a poly fused
heterocycle thiazolobenzimidazole fused dihydropyran
derivatives in excellent yields from readily available simple
starting materials. The heterocyclic skeleton obtained in this
study may have interesting biological properties.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors thank DST, New Delhi for assistance under the IRHPA
program for the NMR facility. SM acknowledges CSIR, New Delhi for
the award of Emeritus Scientist Scheme.
Fig. 2 X-ray structure of 4k
Notes and references
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It must be indicated that there were no recognizable
products from the reaction mixture when we perform the
reaction with other active methylene compounds such as
diethyl malonate and ethyl acetoacetate. Propionaldehyde and
acetaldehyde were tried in the place of arylaldehyde, but the
reactions did not yield any recognizable products.
2
3
4
5
6
7
8
The plausible mechanism for the formation of 4, based on
the sequential addition, is given in scheme 3. Initially the
formation of enone occurs with the dehydration affording
The subsequent Michael addition of malononitrile affords 1,4
addition adduct The anion generated via the
A.
B.
C
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17 CCDC Number for compound 4k is 1497336.
4 | J. Name., 2012, 00, 1-3
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