NBS mediated protocol for the synthesis of N-bridged fused heterocycles in water

Article abstract of DOI:10.1016/j.tetlet.2017.08.017

A facile and environmental friendly protocol for the synthesis of N-bridged fused bicyclic compounds such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[2,1-b]thiazole, from commercially available starting materials has been developed.

Full text of DOI:10.1016/j.tetlet.2017.08.017

Accepted Manuscript
NBS mediated protocol for the synthesis of N-bridged fused heterocycles in
water
Saket B. Bhagat, Vikas N. Telvekar
PII:
S0040-4039(17)31006-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.017
TETL 49207
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 June 2017
3 August 2017
7 August 2017
Please cite this article as: Bhagat, S.B., Telvekar, V.N., NBS mediated protocol for the synthesis of N-bridged fused
heterocycles in water, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.017
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Graphical Abstract
NBS mediated protocol for the synthesis of
N-bridged fused heterocycles in water
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Saket B. Bhagat, Vikas N. Telvekar*

2
Tetrahedron Letters
journal homepage: www.elsevier.c om
NBS mediated protocol for the synthesis of N-bridged fused heterocycles in water
Saket B. Bhagat, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga,
Mumbai-400 019, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and environmental friendly protocol for the synthesis of N-bridged fused bicyclic
compounds such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and
imidazo[2,1-b]thiazole, from commercially available starting materials has been
developed. The reaction proceeds via NBS mediated in situ formation of α-brominated
intermediate of corresponding aromatic ketones, 1,3-diketones, β-keto esters, followed by
trapping with suitable nucleophiles to provide these versatile imidazole fused bicyclic
heterocycles in good yields under metal-free conditions.
Available online
Keywords:
Heterocycle
diketone
NBS
-
Water
N
N
N
N
N
The bridgehead nitrogen heterocycles, especially the fused
imidazoles like imidazo[1,2-a]pyridines, imidazo[1,2-
a]pyrimidines, and imidazo[2,1-b]thiazole, are an important class
of privileged structural motifs in bioactive compounds,
pharmaceuticals and organic functional materials. Amongst them,
Cl
N
N
N
Cl
O
O
N
Nicopidem
iBu
Zolpidem
O
Alpidem
CN
N
N
O
S
O
Cl
N
imidazo[1,2-a]pyridines exhibit
a
plethora of biological
N
HN
N
N
O
properties displayed over a broad range of therapeutic classes;
including antibacterial, antifungal, antiviral, antiulcer, anti-
Zolimidine
N
Saripidem
CH3
N
N
nPr
Oliprinone
O
N
inflammatory,
β-amyloid
formation
inhibitors,
N
S
N
N
immunosuppressive, GABA receptor agonists, cardiotonic
agents, and nonpeptide B
motif imidazo[1,2-a]pyridine is an important ring system that has
S
N
PO(OH)2
PO(OH)2
N
1
N .HCl
Levamisole
N
2
receptor antagonists. This structural
N
N
OH
OH
Minodronic acid
O
NEt2 .HCl
YM-201627
GSK812397
been successfully developed into commercially marketed drugs
2
such as Alpidem, Zolpidem etc (Fig 1).
Figure 1. Commercial drugs on imidazo[1,2-a]pyridine/imidazo[2,1-
b]thiazole
Another fused imidazoles heterocycle which has gained much
focus is imidazo[2,1-b]thiazole. The imidazo[2,1-b]thiazole is an
attractive scaffold found in many natural products and
biologically active compounds as antibacterial, antitubercular,
antifungal, anthelmintic, antiinflammatory, and antitumor
such as 2-aminopyridines with various compounds, such as α-
6
7
8
9
halocarbonyl,
1,3-dicarbonyl,
nitroolefins,
alkynes,
10
11
12
diazoketones, 1,2-diols, 1-chloromethyl-benzotriazole, 1,2-
13
3
bis (benzotriazolyl)-1,2-(dialkylamino)-ethanes. Also, 2-halo-1-
agents. The imidazo[2,1-b]thiazole system constitutes the main
phenacyl/alkyl pyridinium salts, pyridinium azomethine ylides,
part of the well-known antihelmintic-immuno modulatory agent
such as Levamisole. Also, YM-201627, benzo[d]imidazo[2,1-
b]thiazoles derivative, has been reported as a potent orally active
and other derivatives have been explored as precursors for
14
construction of these heterocycles.
The imidazopyridine
4
nucleus have reportedly been synthesized from substituted
antitumor agent. The versatility of these N-heterocycles has
15
imidazoles too. A multi-component approach involving one-pot
prompted great interest in the development of novel and efficient
methodologies to gain an easy access to these bicyclic ring
condensations of 2-aminopyridines, aldehydes, and isonitriles,
16
5
also referred as Groebke-Blackburn-Bienayme reaction.
systems. The most widely used approach for the synthesis of
Recently, this ring system has also been synthesized from 2-
aminopyridine and 1,3-dicarbonyl compounds using reagents
such as CBr and CBrCl , however, these polyhalogenated
4 3
imidazo[1,2-a]pyridines involves the construction of imidazole
rings by cyclocondensation of suitably substituted pyridine
precursors
reagents are known environmental hazards and the reaction
requires a strong base, organic solvent, long reaction time, thus
_
*
____________
Corresponding author. Tel.: +91 22 3361 2213; fax: +91 22 3361 1020.
17
limiting the utility of these protocols.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).

Although elegant processes have been reported, the traditional
method for the construction of this scaffold involves
condensation of 2-aminopyridines with α-halocarbonyl
compounds both at laboratory and industrial scale. However, the
commercial availability of only small variety of α-halocarbonyl
compounds, their stability and their lachrymatory properties
severely restrict the utility of this process. Thus, there is an
intrinsic need to develop a simpler, practical and atom-
economical synthesis of these significant bioactive motifs from
simple precursors. Compared to pre-activated ketones, the use of
unactivated ketones as starting substrates for imidazo[1,2-
a]pyridine synthesis is highly desirable.
With the above optimized reaction condition in hand, the scope
of the methodology was investigated and the results are
summarized in Table 2.
1
8
a
Table 2. Synthesis of N-bridged fused heterocycles
Entry
Amine
1)
Ketone
(2)
Product
(3)
Yield
(%)
(
1
91
2
3
4
86
94
89
Our approach is to activate the ketones, followed by their
reaction with appropriate nucleophiles to provide a diverse range
of these heterocycles in one step. Thus, in continuation of our
interest on the exploration of novel environment friendly
approaches in synthetic organic chemistry, we report herein a
NBS mediated, method for the construction of N-bridged fused
heterocycles from readily available starting material using water
as a solvent.
5
6
7
8
9
84
78
81
83
94
N
Cl
N
The study was initiated by using 2-aminopyridine (1a) and ethyl
acetoacetate (2a) as model substrates in presence of NBS to
optimize the reaction conditions. No reaction was observed in
water at room temperature even after 24h (Table 1, entry 1), but,
when the reaction was performed at elevated temperature (80
°
1
C), the product 3a was obtained in 35% yield within 6 h (Table
, entry 2). Furthermore, the use of other solvent such as EtOH,
MeOH, MeCN and CCl , did not have any noteworthy impact on
10
92
87
4
the yield of 3a (Table 1, entries 3-6). However, the yield of the
desired product 3a was significantly improved when ethyl
acetoacetate (2a) was first reacted with NBS at 80 °C in water for
1
1
3
0 min, followed by the addition of 2-aminopyridine (1a) and
heating at 80 °C for another 30 min (Table 1, entry 7). A further
decrease in the temperature to 60 °C had detrimental impact on
the yield of 3a (Table 1, entry 8), while bringing the temperature
to reflux did not advance the yield of 3a (Table 1, entry 9). Thus,
it was determined that NBS (1.2 equiv) at 80 °C in water were
the optimal reaction conditions for this transformation (Table 1,
entry 7).
12
80
71
1
1
3
4
67
70
64
61
a
Table 1. Screening of the reaction conditions
1
1
5
6
c
Entry
Solvent
Temperature
RT
Yield (%)
1
2
3
4
5
6
H
H
2
O
2
O
NR
35
30
25
15
40
91
60
88
17
80 °C
EtOH
MeOH
Reflux
Reflux
Reflux
Reflux
80 °C
a
CH
3
CN
Reaction conditions: 1.05 mmol of β-diketones/β-keto esters/aryl
ketones, 1.2 mmol of NBS in water at 80 °C for 30 min, followed by
addition of 1.0 mmol of appropriate nucleophile and heating at 80 °C.
Isolated yields after column chromatography and the structures were
confirmed by comparison of IR, H NMR and M.P. with literature.
CCl
4
b
7
8
9
H
H
H
2
O
2
O
2
O
b
b
60 °C
Reflux
1
b
a
Reaction conditions: 2-aminopyridine (1a, 1.0 mmol), ethyl acetoacetate
2a, 1.05 mmol), NBS (1.2 mmol) in water (5.0 mL). Ethyl acetoacetate
2a, 1.05 mmol), NBS (1.2 mmol) in water (5.0 mL) heated for 30 min.
b
(
(
The reaction of 2-aminopyridine (2a) with various β–keto esters
and 1,3-diketones, gave the corresponding products smoothly in
good to excellent yields (Table 2, entries 1-4). Next, 2-
aminopyridine was reacted with aryl methyl ketones bearing an
electron withdrawing or an electron donating substituent on the
phenyl ring, the corresponding product was obtained in good
yield in all the cases (Table 2, entries 5-7). Encouraged by this
Subsequently, 2-aminopyridine (1a, 1.0 mmol) was added to this reaction
mixture, heated until the disappearance of 2a, monitored by TLC.
c
Isolated yield. NR: no reaction.

4
Tetrahedron
result, 2-aminopyridine was reacted with heteroaryl ketone, viz
-acetylthiophene, which also furnished the desired product in
of the reaction and the commercial availability of the starting
materials and the promoter. The method is advantageous in terms
of its high efficiency, mild reaction conditions, operational
simplicity, absence of expensive transition metal catalyst or toxic
solvents, the ease of product isolation, and the higher yield.
2
good yield (Table 2, entry 8). To further expand the substrate
scope, substituted 2-aminopyridine were subjected to the reaction
condition. Reaction of 3-methyl and 4-methyl-2-aminopyridines
with β–keto esters, 1,3-diketones and aryl methyl ketones,
afforded the corresponding imidazo[1,2-a]pyridines in good to
moderate yield (Table 2, entries 9-12). Next, we shifted to
investigate the scope of other nucleophiles, such as 2-
aminopyrimidine, 2-aminothiazole and 2-aminobenzothiazole.
These heterocycles did not affect the overall efficiency of the
reaction and the corresponding products 3m–3q were furnished
in good to moderate yields (Table 2, entries 13-17).
Acknowledgment
SBB is thankful to the University Grants Commission (UGC, New
Delhi, India) for providing fellowship and VNT is thankful for
financial support under UGC major research scheme.
References
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2
a was reacted with NBS under the present optimised reaction
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Scheme 1, taking the reaction of 2-aminopyridine 1a and ethyl
acetoacetate 2a for the synthesis of imidazo[1,2-a]pyridine 3a as
an example. As depicted in Scheme 1, 2a is first brominated with
NBS in water to give intermediate A. The in situ generated
intermediate
A underwent an intermolecular nucleophilic
substitution reaction with 2-aminopyridine 2a to obtain
intermediate B. Finally, intermediate B further underwent an
intramolecular cyclization to afford the desired product
imidazo[1,2-a]pyridine 3a.
2
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2
007, 7, 888.
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.
3
a in a comparable yield (82%).
2
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1
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S
2
1
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In conclusion, an NBS-mediated one-pot strategy in water has
been proposed for the synthesis of N-bridged fused bicyclic
heterocycles. The process involves the reaction of 2-
aminopyridines, or 2-aminopyrimidines, or 2-aminothiazole, with
β-keto esters, or 1,3-diones, or aryl ketones, to construct
imidazo[1,2-a]pyridines, or imidazo[1,2-a]pyrimidines, or
imidazo[2,1-b]thiazole, respectively. It is notable that the present
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8
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9
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(d, J = 8.9 Hz, 1H), 7.36 – 7.33 (m, 1H), 6.94 (t, J = 6.7 Hz, 1H), 4.41 (q,
13
J = 7.0 Hz, 2H), 2.70 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H). C NMR (100
MHz, CDCl ) δ ppm 161.7, 152.0, 146.1, 127.2, 126.7, 115.9, 112.6,
111.4, 59.5, 16.0, 13.5. MS (ESI) m/z: 205 [M+H] .
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3
+
1
1
1
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1
9
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-
1
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1
1
993, 22, 1317.
3
2930, 1634, 1370, 1246, 739. H NMR (400 MHz, CDCl ) δ ppm 8.09 (d,
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1
1
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3
1H), 6.77 (t, J = 6.7 Hz, 1H). C NMR (100 MHz, CDCl ) δ ppm 145.7,
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+
(ESI) m/z: 195 [M+H] .
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1
2
-
Yellowish white solid, mp 136-138 °C (lit.mp 137-139 °C). IR (KBr, cm
1
1
(
d) Artyomov, V. A.; Shestopalov, A. M.; Livinov, V. P.
3
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1
3
2
317.
3
7.10-7.06 (m, 1H), 6.72 (t, J = 6.8 Hz, 1H). C NMR (100 MHz, CDCl )
1
1
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+
112.4, 107.3. MS (ESI) m/z: 201 [M+H] .
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1151; (c) Knolker, H.-J.; Boese, R.; Hitzemann, R. Heterocycles
1
7
1
989, 29, 1551; (d) Knolker, H.-J.; Boese, R.; Hitzemann, R.
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-
1
1
Chem. Ber. 1990, 123, 327; (e) Knolker, H.-J.; Hitzemann, R.
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Hz, 1H), 7.06 (dd, J = 6.8, 4.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.78 (s,
3
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P. M. S. J. Org. Chem. 2012, 77, 1414; (k) Khan, A. T.; Basha,
R. S.; Lal, M. Tetrahedron Lett. 2012, 53, 2211; (l) Sun, H.;
Zhou, H.; Khorev, O.; Jiang, R.; Yu, T.; Wang, X.; Du, Y.; Ma,
Y.; Meng, T.; Shen, J. J. Org. Chem. 2012, 77, 10745; (m)
Kishore, K. G.; Basavanag, U. M. V.; Islas-Ja´come, A.;
Ga´mez-Montan˜o, R. Tetrahedron Lett. 2015, 56, 155; (n)
Chernyak, N.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49,
1
3
3
3H), 1.45 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl ) δ ppm 161.2,
154.7, 151.6, 149.5, 135.5, 111.2, 109.9, 60.5, 16.6, 14.3. MS (ESI) m/z:
+
206 [M+H] .
1
9
6-Phenylimidazo[2,1-b]thiazole 3p (Table 2, entry 16): Yellow solid,
mp 147-149 °C (lit. mp 148-149 °C). IR (KBr, cm ) vmax 1554, 1536,
1466, 1191, 772, 724. H NMR (400 MHz, CDCl
-1
1
3
) δ ppm 8.21 (s, 1H),
7.93 (d, J = 4.2 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz,
1
3
3
2H), 7.27 (d, J = 4.7 Hz, 2H). C NMR (100 MHz, CDCl ) δ ppm 150.2,
147.8, 134.0, 128.4, 127.3, 125.1, 118.4, 112.4, 107.9. MS (ESI) m/z:
+
201 [M+H] .
19. (a) Zhu, D.-J.; Chen, J.-X.; Liu, M.-C.; Ding, J.-C.; Wu, H.-Y. J.
Braz. Chem. Soc. 2009, 20, 482; (b) Cai, Z.-J.; Wang, S.-Y.; Ji,
S.-J. Adv. Synth. Catal. 2013, 355, 2686.
2
743; (o) Palani, T.; Park, K.; Kumar, M. R.; Jung, H. M.; Lee,
S. Eur. J. Org. Chem. 2012, 5038.
1
1
7. (a) Huo, C.; Tang, J.; Xie, H.; Wang, Y.; Dong, J. Org. Lett.
2
016, 18, 1016; (b) Roslan, I. I.; Ng, K.-H.; Chuah, G.-K.;
Jaenicke, S. Adv. Synth. Catal. 2016, 358, 364.
8. Typical Procedure for the Synthesis of imidazo[1,2-
a]pyridine/imidazo[1,2-a]pyrimidine/imidazo[2,1-b]thiazole
(
3): To a round bottom flask containing 1,3-diketones/β-keto
esters/aryl ketones (1.05 mmol) and water (5 mL) was added
NBS (1.2 mmol) and mixture was allowed to stir at 80 °C for 30
min. Subsequently, 2-aminopyridine/2-aminopyrimidine/2-
aminothiazole (1.0 mmol) was added and reaction mixture was
further heated to 80 °C for 30 min. After completion of reaction
(
checked by TLC), it was allowed to cool to room temperature
and then the mixture was poured into 10 mL of sodium
carbonate solution. The reaction mixture was extracted with
ethyl acetate (3 x 20 mL). The combined organic layer was
washed with water, saturated brine solution, dried over
anhydrous Na SO and concentrated in vaccuo. The resulting
2 4
crude product was purified by silica gel column
chromatography with petroleum ether–ethyl acetate to give
corresponding
imidazo[1,2-a]pyridine/imidazo[1,2-
a]pyrimidine/imidazo[2,1-b]thiazole.
Ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate 3a (Table 2,
1
7
-1
entry 1): White solid, mp 66-68 °C (lit. mp 68-70 °C). IR (KBr, cm )
max 3410, 3145, 2999, 1678, 1595, 1490, 1411, 1296, 1222, 1094, 850,
7
v
1
3
61. H NMR (400 MHz, CDCl ) δ ppm 9.29 (d, J = 6.9 Hz, 1H), 7.59

6
Tetrahedron
•
Synthesis of N-bridged fused bicyclic compounds
from commercially available starting materials has
been developed
•
•
•
The reaction is performed with readily available
starting materials with broad substrate scope
This reaction proceeds via NBS mediation
bromination of ketones and β-ketoesters
Reaction is metal free and water is used as a green
solvent