One pot synthesis of substituted imidazopyridines and thiazoles from styrenes in water assisted by NBS

Article abstract of DOI:10.1039/c5gc02771c

Heating of commercially available styrenes with NBS in water followed by reaction with 2-aminopyridines or thioamides afforded important heterocyclic scaffolds in a one pot procedure. The reaction proceeds via co-oxidant free, in situ formation of α-bromoketone using NBS as a bromine source as well as an oxidant followed by trapping with suitable nucleophiles to provide imidazopyridines and thiazoles.

Full text of DOI:10.1039/c5gc02771c

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DOI: 10.1039/C5GC02771C
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One Pot Synthesis of Substituted Imidazopyridines and Thiazoles
from Styrenes in Water Assisted by NBS
Received 00th January 20xx,
Accepted 00th January 20xx
Mahesh H. Shinde and Umesh A. Kshirsagar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: Just heating of commercially available styrenes with NBS
in water followed by reaction with 2-aminopyridines and
thioamides, important heterocyclic scaffold were prepared in one
pot manner. Reaction proceed via co-oxidant free, in-situ
formation of α-bromoketone using NBS as bromine source as well
as oxidant followed by trapping with suitable nuclephiles to
provide imidazopyridines and thiazoles.
Nitrogen and sulphur containing privileged heterocyclic
scaffolds such as Imidazo[1,2-a]pyridines and thiazoles plays
an important role in the modern synthetic and medicinal
chemistry due to their promising biological and
pharmaceutical activities.1 Of particular, imidazo[1,2-
a]pyridine is important motif due to presence in various top
commercial drugs such as zolpidem, zolimidine, olprinone,
GSK812397, anxiolytic agents alpidem, necopidem, saripidem
Figure 1. Selected commercial drugs based on imidazo[1,2-a]pyridine and thiazole.
(Figure 1).2 Imidazo[1,2-a]pyridines also have applications in N- involves the use of toxic bromine sources.9 Donohoe group
heterocyclic carbene chemistry3 and material chemistry.4 The
recently reported two step approach for the synthesis of these
thiazole nucleus is present in several biologically active natural heterocycles from alkenes which involves the preparation of α-
products such as epothilone, leinamycin, barakacin.5 iodoketone by reaction of olefins with IBX/Iodine in DMSO and
these α-iodoketones were treated with suitable nucleophiles
Numerous thiazole based drug are also known such as
ritonavir, abafungin, sulfathiazole.6 Various synthetic methods in the presence of K2CO3/DMF to give the diverse
have been reported for the construction of these motifs such heterocycles.10
Use of the water as solvent for organic reactions is the most
as C-H amination, oxidative cyclization, multicomponent
reaction, hydroamination and tandem processes from various interesting and attracted step because of its economic and
starting materials.7 Most of these reaction are metal catalysed
and/or use of oxidants. Traditional method for the
construction of these scaffolds includes condensation of α-
haloketones with suitable nucleophiles in the various organic
solvents and bases which involves the heating for longer time
(Scheme 1).8 Most stern issue is the handling of lachrymatic
phenacyl bromides or their analogues. In-situ preparation of α-
haloketones from ketone are also known in literature but
Scheme 1. Approach for the synthesis imidazo[1,2-a]pyridine and thiazole.
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environmentally friendly nature.11 NBS has numerous H2O:dioxane to H2O:acetonitrile or H2O:acetone, decrease in
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DOI: 10.1039/C5GC02771C
applications in the synthetic organic chemistry such as simple the yield was observed (entry 7/8). To our delight, when
and non-toxic cationic and radical bromine source as well as reaction was performed using only water as solvent, it
oxidant.12 In view of this, here we would like to report the NBS furnished the imidazo[1,2-a]pyridine 2a in 89% yield (entry 9).
promoted, simple, one pot method for the construction of
diverse heterocyclic building blocks in water as solvent from
commercially available styrenes without using co-oxidant. NBS
plays dual role such as safe bromine source and oxidant,
whereas reaction was carried out using water which also act as
‘O’ source for the in-situ preparation α-bromoketones. These
in-situ formed α-bromoketones upon reacting with
appropriate nucleophiles in one pot manner provided the
diverse heterocycles.
We initiated the optimization of reaction on simple styrene
(1a) (table 1). Reaction of styrene 1a with iodine in the
presence of tert-butyl hydroperoxide (TBHP, entry 1) or 2-
iodoxybenzoic acid (IBX, entry 2) as oxidant in DCE and DMSO
as solvent at 40 oC or 80 oC followed by addition of 2-
aminopyridine gave the desired imidazo[1,2-a]pyridine 2a
product in very trace amount. Treatment of styrene with other
iodine source, N-iodosuccinimide (NIS) in the presence of IBX
as oxidant in DMSO at 40 oC followed by addition of 2-
aminopyridine provided desired imidazo[1,2-a]pyridine 2a in
30% yield (entry 3). When same reaction was carried out at
higher temperature, yield was not improved significantly. Use
of KI in the presence of oxone was unable to give the desired
product (entry 4) but KI in the presence of K2S2O8 provided the
imidazo[1,2-a]pyridine 2a in 35% yield (entry 5). Treatment of
styrene (1a, 1.0 equiv.) with NBS (2.0 equiv.) in H2O:dioxane at
Scheme 2. Possible reaction pathway.
Reaction includes the NBS/H2O promoted formation of
bromohydrin (B) followed by NBS mediated oxidation of
secondary benzylic alcohol for the in-situ formation of
phenacyl bromide (D) (Scheme 2). Condensation of phenacyl
bromide with 2-aminopyridine furnished the desired product
imidazo[1,2-a]pyridine 2. No improvement in the yield was
observed by portion wise addition of NBS (entry 10). When
NBS was replaced with NIS, it gave the compound 2a in 32%
yield (entry 11) whereas with NCS, formation of 2a was not
observed (entry 12). We have also screened other bromine
sources such as molecular bromine and tetrabutylammonium
bromide (TBAB) using air as oxidant but formation of 2a was
not observed (entry 13/14).
o
80 C for 1.2 hr followed by addition of 2-aminopyridine gave
Having optimized condition in hand, we pursued for the
exploration of substrate scope. Reacting NBS with aryl olefin
with electron withdrawing groups on aromatic ring such as -F
and -Br (1b,c) provided corresponding imidazo[1,2-a]pyridine
(2b,c) smoothly in very good yields (82 and 81%). Styrenes
the imidazo[1,2-a]pyridine 2a in 41% yield after heating at 80
oC for 2 hr (entry 6). Change in the solvent system from
Table 1. Optimization of the reaction condition.a
entry
1
2
3
4
5
6
7
8
Solvent
DCE
DMSO
X-source
I2
I2
NIS
KI
oxidant
2a (%)b
Trace
Trace
30%
00%
35%
41
33
15
89
78
TBHP
IBX
IBX
oxone
K2S2O8
-
-
-
-
-
-
-
air
air
DMSO
DMSO:H2O
CH3CN:H2O
H2O:dioxane
H2O:CH3CN
H2O: acetone
H2O
KI
NBS
NBS
NBS
NBS
NBS
NCS
NIS
Br2
9
10c
11
12
13
14
H2O
H2O
H2O
H2O
00
40
00
00
H2O
TBAB
[a] Condition: Styrene (1 mmol), X-source (2 mmol), oxidant (2 mmol), solvent
(2 mL), 80 oC, 1.2 hr, then 2-aminopyridine (2.0 mmol), 80 oC, 2 hr. [b] isolated
yields, [c] NBS was added in two portions at 30 min. interval.
Figure 2. Substrate scope for the imidazo[1,2-a]pyridines.
2 | J. Name., 2012, 00, 1-3
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with electron releasing groups such as 4-methyl and 4-tert- 4-fluoro-styrene, it provided corresponding interesting 2,4-
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DOI: 10.1039/C5GC02771C
butyl also afforded the corresponding imidazo[1,2-a]pyridine diarylsubstituted thiazoles (3h,i) in very good yields (72 and
(2d,e) in very good yield (79 and 75%). Use of 2-amino-5- 75%). Thiourea was also explored as nucleophilic partner with
bromo-pyridine as nucleophilic partner with styrene afforded styrene (1a) to give the 2-amino-4-phenylthiazole (3j) in 63%
imidazo[1,2-a]pyridine (2f) in 85% yield. Reaction of 4- yield. Starting from
β-methyl styrenes, highly substituted
methoxystyrene with NBS followed by 2-aminopyridine thiazoles (3k-m) were prepared. To afford these 2,4,5-
provided complex reaction mixture. Reaction with 4-methyl trisubstituted thiazoles (3k-m) in moderate yields (67-58%)
and 5-methyl-2-aminopyridines afforded corresponding from β-methyl styrene and β-methyl-4-nitro-styrene required
imidazo[1,2-a]pyridine (2g,h) in good to moderate yield (78 longer time (7 hrs) heating prior the addition of thiourea and
and 73%). Styrene having strong electron withdrawing group thiobenzamide.
such as NO2 works smoothly to afford the corresponding
imidazo[1,2-a]pyridine (2i) in 72% yield.
Conclusions
Encouraged by preparing various imidazo[1,2-a]pyridine we
shifted to investigate the scope of other nucleophiles.
Thioamide was selected as next nucleophilic partner for
condensation due to its potential for the formation of
thiazoles. Reaction of various styrenes such as styrene (1a) and
halo substituted styrenes with NBS and subsequent addition of
thiobenzamide in water provided 2,4-diarylsubstituted
thiazoles (3a-d) in good yields (70-77%). Reaction of alkyl
substituted styrene such as methyl and tert-butyl styrene with
thiobenzamide provided corresponding thiazoles (3e,f) in 70
and 73% yield. Scope of different thioamides has also been
checked. Use of thioacetamide as condensing partner with
styrene (1a) provided corresponding 2-methyl-4-phenyl
thiazoles (3g) in good yields (67%). When thionicotinamide
was used as nucleophilic partner with styrene (1a) and
In conclusion, we have demonstrated the facile one pot
procedure for the synthesis of substituted imidazopyridines
and highly substituted thiazoles starting from important
feedstock such as styrenes promoted by NBS. Reaction
proceeds via formation of α-bromoketone as versatile
intermediate followed by condensation with various
nucleophiles in one pot manner. Reactions were carried out in
water as solvent and are co-oxidant free where the NBS plays
dual role.
Acknowledgements
U.A.K. thanks DST-INDIA, New Delhi for the INSPIRE Faculty
Award (Award No. IFA12-CH-81). We thank Savitribai Phule
Pune University, Pune and Department of Chemistry, SPPU,
Pune for infrastructure facility.
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