Water mediated deprotective intramolecular hydroamination of N-propargylaminopyridines: Synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2013.08.112

Metal-free synthesis of substituted imidazole [1,2-a]pyridines from deprotective N-(prop-2-yn-1-yl)pyridin-2-amines in water is elucidated. Electron releasing substituents on pyridine ring provided pure products in quantitative yields without separation b

Full text of DOI:10.1016/j.tetlet.2013.08.112

Accepted Manuscript
Water mediated deprotective intramolecular hydroamination of N-propargyla‐
minopyridines: synthesis of imidazo[1,2-a]pyridines
Darapaneni Chandra Mohan, Niraj B. Sarang, Subbarayappa Adimurthy
PII:
S0040-4039(13)01510-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.112
TETL 43475
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 July 2013
23 August 2013
27 August 2013
Please cite this article as: Mohan, D.C., Sarang, N.B., Adimurthy, S., Water mediated deprotective intramolecular
hydroamination of N-propargylaminopyridines: synthesis of imidazo[1,2-a]pyridines, Tetrahedron Letters (2013),
doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.112
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Water mediated deprotective intramolecular hydroamination of
N-propargylaminopyridines: synthesis of imidazo[1,2-a]pyridines
Darapaneni Chandra Mohan, Niraj B. Sarang, Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals Research Institute,
G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).E-mail: adimurthy@csmcri.org
Abstract: Metal-free synthesis of substituted imidazole [1,2-a]pyridines from deprotective
N-(prop-2-yn-1-yl)pyridin-2-amines in water is elucidated. Electron releasing substituents on
pyridine ring provided pure products in quantitative yields without separation by column
chromatography.
Keywords: N-Propargylaminopyridines, imidazo [1,2-a]pyridine, hydroamination, synthesis,
water.
Bridged nitrogen heterocyclic compounds are widely found in many biologically active
1
compounds. Among them imidazo-[1,2-a]pyridine scaffolds represent an important class of
organic moieties and are attractive for both synthetic and medicinal chemists due to their
2
3
4
5
antibacterial, antifungal, antiviral, and anti-inflammatory properties. Recently a numerous
6
7
imidazo-[1,2-a]pyridine based drugs have been developed such as alpidem, olprinone,

8
9
minodronic acid (to treat anxiety, heart failure and osteoporosis), zolimidine (peptic ulcer),
1
0
necopidem, saripidem (sedative and anxiolytic) and optically active GSK812397 candidate
11
(
HIV Infection) are derived (Figure 1). In addition, imidazo-[1,2-a]pyridine derivatives
1
2
received considerable attention in the field of material chemistry as sensor devises. Because
of such appealing applications of imidazo-[1,2-a]pyridines recently a variety of synthetic
1
3
methods have been developed including intermolecular diamination of alkynes, oxidative
1
4
15
cross-coupling/cyclization, three-component coupling reaction of alkynes, Cu(I)-catalyzed
1
6
17
method, tetrabutylammonium iodide oxidative coupling, Morita-Baylis -Hillman(MBH)
18
19
reaction and other methods.
1
1
1
1
1
2
2
n
i
2
2
2
1
1
2
2
n
2
3
2
Figure 1. Imidazo[1,2-a]pyridine derived drugs
Since the last two decades the development of synthetic methodologies using benign
solvents/neat and metal-free conditions are encouraged. However, many organic reactions
require a solvent; consequently performing such reactions in water is more attractive and find
2
0
merits over volatile organic solvents. Moreover, water also exhibits unique reactivity and
2
1
selectivity that cannot be attained in conventional organic solvents. Additionally, due to
hydrophobic effects using water as a solvent not only accelerates reaction rate but also
enhances selectivity even when the reactants are sparingly soluble or insoluble in this

2
2
medium. In continuation of our studies on the development of green and sustainable
2
3
methods, we report herein a metal-free water mediated synthesis of substituted
imidazo[1,2-a]pyridines from deprotective tert-butyl prop-2-yn-1-yl(pyridin-2-yl)carbamates
2
4
(Scheme 1).
Scheme 1
We are interested in transforming BOC-protected aminopyridines, such as 1a, into imidazo
1,2-a]pyridines without the need for any extra deprotection step; therefore we explored
[
various conditions to accomplish this reaction in one step. We initiated our studies with tert-
butyl prop-2-yn-1-yl (pyridin-2-yl) carbamate 1a as a substrate to optimize the reaction
conditions (Table 1). Initially, the reaction was performed in water at room temperature; no
product formation was observed (Table 1, entry 1). When the reaction carried out at 60 °C,
the desired product 2a was isolated in 35% yield in 24 h (Table 1, entry 2). A clear
improvement of the yield was observed when the reaction temperature was raised from 60 °C
to 120 °C (Table 1, entries 3−6). Performing the reaction under argon atmosphere instead of
open air at 120 °C, 98% yield of 2a was isolated (Table 1, entry 7). Though organic substrates
are insoluble in water at room temperature, at high temperature water may exhibit acidic
character and reaction proceeds at that temperature. When the reaction performed under open

atmosphere at 120 °C, some amount of substrate charring was observed (Table 1, entry 6).
Reactions in other solvents were either poorly effective or entirely ineffective (Table 1, entry
8
-12). To the best of our knowledge, this is the first report on water mediated deprotective
intramolecular hydroamination in the absence of metal and organic solvent.
a
Table 1 Optimization of reaction conditions
o
2
2
2
2
2
2
2
3
a
Reaction conditions: 1a (1 mmol), solvent (4 mL), in a sealed tube; isolated yield.
The scope of this methodology was then extended for the synthesis of a variety of substituted
2
5
imidazo[1,2-a]pyridines 2 (Table 2). The substituted tert-butyl prop-2-yn-1- yl (pyridin-2-
24b
yl)carbamate starting materials 1 were readily prepared by following literature procedure.
Notably, the products 2a-2e were obtained in quantitative yields without subjecting to column
chromatography. The presence of a variety of electron-withdrawing groups (Ph and Cl)

provided the corresponding methyl imidazo[1,2-a]pyridines 2f and 2g in moderate to good
yields. These moderate yields may be due to lowering of electron density on pyridine ring. In
addition, phenyl substituted at terminal alkynes also underwent this transformation and
a
Table 2 Scope for syntheses of 2
a
b
2
Reaction conditions; 1a (0.1 mmol), H O (4 mL), oil bath in a sealed tube. Isolated yield.
generated corresponding imidazo[1,2-a]pyridine 2h and 2i in 95% and 62% yields
respectively. Interestingly, tert-butylprop-2-yn-1-yl(pyrazin-2-yl)carbamate also displayed a
good reactivity and yield the product 3-methylimidazo[1,2-a]pyrazine 2j in 54% yield. Based
2
3a
on the above observations and literature reports a probable mechanism is proposed

(Scheme 2). Initially, tert-butylprop-2-yn-1-yl-(pyridin-2-yl)carbamate 1a in presence of
water form hydrogen bonds (intermediate I) and undergo intramolecular hydroamination
2
3a
through 5-exo-dig cyclization yield the intermediate II. Subsequently, II abstracts proton
from water through 1, 3 prototrophic shifts provide the final product 2a.
H
O
H
O
H
H
H
O
O
H
H
O
O
H
O
O
N
Water(H O)
2
R
N
N
H
O
1a
H
N
H
R
H
O
H
I
O
H
Water(H O)
2
H
5-exo-dig cyclization
H
H
N
O
N
H
1,3-prototropic shift
N
H
R
through solvent
O
N
H
2a
H
H
II
R
H
H
H
O
O
H
H
H
O
H
Scheme 2. Probable mechanism for synthesis of 2a.
In summary, we reported the synthesis of imidazo[1,2-a]pyridine from deprotective N-(prop-
-yn-1-yl)pyridin-2-amines through intramolecular hydroamination using water as a solvent
2
and catalyst. Through this method moderate to excellent yields of desired products could be
obtained. The method is also applicable for the synthesis of 3-methylimidazo[1,2-a]pyrazine.
Acknowledgments
We thank Dr. A.V. Boricha/Mr B. M. Bhil, and Mr. Arun K Das of this institute for recording
NMR and mass respectively. D.C.M is thankful to UGC New Delhi, India for his fellowship.

DST, Govt. India (SR/S1/OC-13/2011) and CSIR (CSC-0123) are acknowledged for the
financial support.
Supporting information available: Characterization data and copies of NMR spectra for all
compounds.
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25. Synthesis of imidazo[1,2- ]pyridines 2: In a 10 mL round bottomed flask, 1.0 mmol of 1
and 4 mL of water were placed. The flask was purged with argon gas and tightly sealed. The
reaction flask was then heated to 120°C for specified period of time (Table 2) in an oil bath.
After room temperature, the mixture was poured into 20 mL of saturated NaHCO
the product was extracted with dichloromethane (DCM) (20 mL × 3), followed by drying
with anhydrous Na SO . The left out residue after the removal of organic solvent under
3
solution,
2
4
reduced pressure was purified by column chromatography using silica gel to obtain the
desired product 2. [Note: The products 2a-2e were obtained pure (by NMR) without
separation by column chromatography, but by simple extraction and removal of DCM].

Graphical Abstract
Water mediated deprotective intramolecular hydroamination of
N-propargylaminopyridines: synthesis of imidazo[1,2-a]pyridines
Darapaneni Chandra Mohan, Niraj B. Sarang, Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
e-mail: adimurthy@csmcri.org
Abstract: Metal-free synthesis of substituted imidazole[1,2-a]pyridines from deprotective N-
(prop-2-yn-1-yl)pyridin-2-amines in water. Electron releasing substituents on pyridine ring
provided pure products in quantitative yields without separation by column chromatography.
Keywords: N-Propargylaminopyridines, imidazo[1,2-a]pyridine, hydroamination, synthesis,
water.