Switching the regioselectivity in the copper-catalyzed synthesis of iodoimidazo[1,2-: A] pyridines

Article abstract of DOI:10.1039/c6ob00656f

A unique copper-catalyzed binucleophilic switching of 2-aminopyridine has been developed for the regioselective synthesis of 2- and 3-iodoimidazo[1,2-a]pyridines using alkenes/alkynes as coupling partners in the presence of molecular iodine under aerobic

Full text of DOI:10.1039/c6ob00656f

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Switching the regioselectivity in the copper-catalyzed synthesis of
iodoimidazo[1,2-a]pyridines
Dedicated to Prof. Eiichi Nakamura on his occasion of 65th birthday
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Sadhanendu Samanta, Sourav Jana, Susmita Mondal, Kamarul Monir, Swapan K. Chandra and
Alakananda Hajra*
www.rsc.org/
A unique copper-catalyzed binucleophilic switching of 2-aminopyridine has been developed for the regioselective
synthesis of 2- and 3-iodoimidazo[1,2-a]pyridines using alkene/alkyne as coupling partners in the presence of molecular
iodine under aerobic reaction conditions. This method was also applied to the synthesis of 2-iodo-3-
phenylbenzo[d]imidazo[2,1-b]thiazoles. This protocol offers an easy access towards the synthesis of 2,3-diarylimidazo[1,2-
a]pyridines.
is in high demand for the regio-divergent synthesis of
Introduction
halosubstitutedimidazo[1,2-a]pyridines
employing
easily
accessible starting materials under mild reaction conditions.
The majority of the reported methodologies for the synthesis
of imidazo[1,2-a]pyridines have been developed employing
binucleophilic 2-aminopyridine as the starting material. Due to
the presence of two different nitrogen centers, 2-
aminopyridine can react through either endocyclic or exocyclic
nitrogen centre, as a consequence a regioselective product is
obtained under the selective reaction conditions.3e,f It is
worthy to mention that the synthesis of 2-functionalized
imidazo[1,2-a]pyridines are limited so far.3f,h Therefore, we
became interested for a protocol which can control the
regioselectivity in the synthesis of functionalized imidazo[1,2-
a]pyridine moiety under the same reaction conditions.
Imidazo[1,2-a]pyridines are the prime target of the synthetic
chemists over the years due to their immense biological and
pharmaceutical activities.1 They have also applications in
material science.2 In addition, a few of them exhibit excited-
state intramolecular proton transfer (ESIPT).2a As
consequence number of methodologies have been
a
a
developed for the synthesis of functionalized imidazo[1,2-
a]pyridines.3 Among the functionalized imidazo[1,2-
a]pyridines, halosubstituted imidazo[1,2-a]pyridines are one of
the important derivatives as these can be further
functionalized through a classical cross-coupling reaction.
However, the synthetic strategies for these derivatives are
very limited so far. These include the (a) oxidative coupling of
During last decade molecular iodine has received considerable
attention due to its availability and immense reactivity to
mediate various reactions such as coupling reaction, C-H
amination, oxidative annulation,electrophilic cyclization etc.8
Recently various heterocycles have also been synthesized
using iodine as a catalyst.9
haloalkynes
with
2-aminopyridines,4
between 2-aminopyridines
(b)
tandem
and
cyclization/iodination
acetophenones,5 (c) halogenation of imidazo[1,2-a]pyridines.6
However, these methods afford either 2- or 3-haloimidazo[1,2-
a]pyridines only. Very recently Zeng et al. reported a tandem
chlorocyclization of 2-aminopyridines with carboxylic acids and
ketones for the synthesis of chlorosubstitutedimidazo[1,2-
From the recent developments on the synthesis and
functionalization of imidazoheterocycles, it is seen that a
regio-divergent method is highly desirable that could provide
both 2- and 3-iododerivatives. In continuation of our interest
a]pyridines.7
Although
this
methodology
provides
regioselective synthesis of 2- or 3-chlorosubstituted
imidazo[1,2-a]pyridines, but it involves the employment of
hazardous reagent. Thus, a versatile and efficient methodology
on imidazo[1,2-a]pyridines10 herein we report
a copper-
catalyzed regioselective synthesis of 2- and 3-iodoimidazo[1,2-
a]pyridines by the coupling between 2-aminopyridine and
alkenes/alkynes in presence of iodine under ambient air
(Scheme 1).
Department of Chemistry, Visva-Bharati (A Central University)
Santiniketan, 731235, West Bengal, India.
E-mail: alakananda.hajra@visva-bharati.ac.in
http://www.visvabharati.ac.in/AlakanandaHajra.html
† Footnotes relaꢀng to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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mmol of I2. dAr atmosphere.
Scheme 1. Change of regioselectivity in the synthesis of imidazo[1,2-a]pyridines.
After getting the optimized reaction conditions we became
interested to explore the substrates scope of this methodology
and the results are represented in the Scheme 2. 2-
Aminopyridine with -Me group at different positions afforded
the corresponding 2-iodo-imidazo[1,2-a]pyridines with almost
Results and discussion
We commenced our study by choosing the reaction between
2-aminopyridine (1a) and phenylacetylene (2a) as the model
substrates. Based on our previous experiences,10a,c,d the
reaction was carried out employing catalytic amount of
equal ease (3ba, 3ca and 3da). 2-Aminopyridines substituted
with halogens like –Cl and –Br also reacted efficiently (3ea and
3fa). Phenylacetylene substituted with –Me and –NO2 also
Cu(OAc)2.H2O (10 mol%) and
1 equiv. of I2 in 1,2-
dichlorobenzene (DCB) at 120 °C in air. Interestingly 2-iodo-3-
phenylimidazo[1,2-a]pyridine (3aa) was obtained with high
yield (82%) after 3 h (Table 1, entry 1). Formation of only one
regioisomer was confirmed by the NMR spectra analysis of
crude product. Inspired by this result we carried out the
reaction under different conditions for the improvement of the
yield and the results are summarized in the Table 1. The
reaction was performed in other common solvents like DMF,
DMSO, toluene, NMP and 1,2-DCE (Table 1, entries 2-6). No
product was obtained in DMF, DMSO and NMP where as much
lower yields were obtained in toluene and DCE. Bases like
K2CO3, KOAc and Et3N were not effective to improve the yield
(Table 1, entries 7-9). Other copper salts like CuI, CuCl,
CuBr.Me2S and Cu(OTf)2 were also tested but these were not
so effective like Cu(OAc)2.H2O (Table 1, entries 10-13). No
significant improvement of yield was observed by increasing
the amount of I2 to 1.5 equiv.; however using 0.5 equiv. of I2
reduced the yield significantly (Table 1, entries 14 and 15).
Much lower yield was obtained under the inert atmosphere
(Table 1, entry 16). Thus optimum yield was obtained by
carrying out the reaction employing 10 mol% Cu(OAc)2.H2O, 1
equiv. I2 in DCB at 120 °C for 3 h under aerobic conditions
(Table 1, entry 1).
gave the product with high yields (3ab, 3cb and 3ac).
Heteroaryl alkyne like 3-ethynylthiophene reacted well under
the optimized reaction conditions (3ad). Different aliphatic
alkynes were also compatible under the reaction conditions
(
3ae
one terminal triple bond and produced 2-iodo-imidazo[1,2-
a]pyridine moiety with a terminal alkyne functionality (3bh
, 3af and 3ag). Interestingly, 1,8-nonadiyne reacted with
)
which could be further functionalized. The structure of 2-Iodo-
5-methyl-3-phenylimidazo[1,2-a]pyridine (3da) was confirmed
by the X-ray crystallography.11
R1
Cu(OAc)2.H2O (10 mol%)
N
I2 (1 equiv.)
R2
R1
+
I
N
I
1,2-DCB, 120 °C, 3 h
air
N
NH2
R2
1
2
3
N
Me
Me
I
N
I
N
N
N
N
3aa, 82%
3ba, 79%
3ca, 78%
N
N
N
Table 1 Optimization of the reaction conditionsa
I
I
I
N
N
N
Br
Cl
Me
3da, 78%
3ea, 74%
3fa, 71%
N
Me
N
N
N
I
I
I
I
N
N
N
N
Entry
1
Catalyst (10 mol%) Solvent Additive
Yield (%)
82
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CuI
1,2-DCB
DMF
S
2
nd
3ab
Me
3cb
3ac
NO2
3ad
, 81%
, 77%
, 81%
, 74%
3
DMSO
nd
Me
4
NMP
nd
Me
N
N
N
N
5
Toluene
1,2-DCE
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
42
I
I
I
N
N
N
6
45
I
N
7
K2CO3
KOAc
Et3N
15
Me
Me
OCOPh
5
3
3
8
18
3ae, 78%
3af, 74%
3ag, 81%
3bh, 78%
5
9
24
10
11
12
13
14
15
16
70
CuCl
64
Scheme 2 Synthesis of 2-iodoimidazo[1,2-a]pyridines.
CuBr.Me2S
<5
Cu(OTf)2
<5
Next we extended our present methodology to 2-
aminobenzothiazoles (Scheme 3). There is no reported method
for the synthesis of 2-halobenzoimidazothiazole derivatives. To
our delight 2-aminobenzothiazoles reacted well under the
present reaction conditions to afford the corresponding 2-
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
81b
55c
11d
aReaction conditions: 0.2 mmol 1a and 0.2 mmol 2a in presence of catalyst
(10 mol%), 0.2 mmol I2 in solvent (2 mL) at 120 °C for 3 h. b0.3 mmol of I2. c0.1
2 | J. Name., 2012, 00, 1-3
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iodobenzo[d]imidazo[2,1-b]thiazoles with good yields after 2.5
5aa 5ba and 5ab). The structure of 2-
h
(
,
iodobenzo[d]imidazo[2,1-b]thiazole (5aa) was confirmed by
the X-ray crystallography.11
Scheme 5 Synthesis of 3-iodoimidazo[1,2-a]pyridines.
Moreover, various 2-phenylimidazo[1,2-a]pyridines were
synthesized using 0.5 equiv. of I2 (Scheme 6). 2-Aminopyridines
with substituents like –Me and –Cl reacted well to give the
corresponding imidazo[1,2-a]pyridines (8ba and 8ea) with
good to high yields. Styrene with different functionalities like –
Me, –OMe, –Cl and –NO2 were well tolerated under the
optimized reaction conditions to produce the respective
Scheme 3 Synthesis of 2-iodobenzo[d]imidazo[2,1-b]thiazoles.
derivatives (8ab, 8ac, 8ad and 8ae).
Next we investigated the coupling of 2-aminopyridine with
styrene under the optimized reaction conditions. Interestingly,
3-iodoimidazo[1,2-a]pyridine derivative (7aa) was obtained as
the major product along with the 2-phenylimidazo[1,2-
a]pyridine
(8aa) after 3 h at 120 °C. After a careful
optimization of the reaction conditions, it was found that the
amount of I2 plays an important role in this conversion. When
the reaction was carried out in the presence of the 1.5 equiv.
of I2, 3-iodoimidazo[1,2-a]pyridine was obtained as the sole
product (Scheme 4, Method A). Whereas the use of 0.5 equiv.
of I2 produced 2-phenylimidazo[1,2-a]pyridine as the single
product (Scheme 4, Method B). This is the beauty of the
current methodology that we could synthesize either 3-
iodoimidazo[1,2-a]pyridines
or
2-phenylimidazo[1,2-
a]pyridines according to our choice only by varying the amount
of I2.
Scheme 6 Synthesis of 2-arylimidazo[1,2-a]pyridines.
The current protocol was also tested for different internal
alkynes (Scheme 7). Gratifyingly diarylacetylenes reacted well
with 2-aminopyridines under the present reaction conditions
to afford the 2,3-diarylimidazo[1,2-a]pyridines with high yields
Scheme
4 Synthesis of 3-iodoimidazo[1,2-a]pyridine and 2-phenylimidazo[1,2-
a]pyridine.
(
10aa, 10ab and 10ba). The reported methods for the one-step
construction of 2,3-diarylimidazo[1,2-a]pyridines are very
limited so far.3k However, unsymmetric diarylacetylenes
produced a mixture of inseparable regioisomers. Internal
alkynes like 4-octyne and 1-phenyl-1-propyne were unreacted
under the present reaction conditions.
Next we explored the scope of reaction employing various
2-aminopyridines with styrene using 1.5 equiv. of I2 (Scheme
5). To our delight the corresponding 3-iodoimidazo[1,2-
a]pyridines were obtained with high yields in all cases (7aa
,
7ba and 7ca). The structure of 3-Iodo-8-methyl-2-
phenylimidazo[1,2-a]pyridine(7ba) was confirmed by the X-ray
crystallography.11
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Scheme 7 Synthesis of 2,3-diarylimidazo[1,2-a]pyridines.
On the basis of the experimental results and literature
reports,4 we propose a mechanism for this reaction (Scheme
8). First, the alkyne reacts with molecular iodine to produce
iodoalkyne. When the reaction was carried out without adding
2-aminopyridine into the reaction mixture, iodoalkyne is
formed under the reaction conditions. Then 2-aminopyridine
reacts with iodoalkyne in presence of Cu(OAc)2 through
endocyclic pyridine nitrogen3f to form the intermediate
A
which is subsequently converted into the Cu(III) complex
B
in
presence of O2.10c,12 Upon reductive elimination the desired
product 3aa is formed. The catalyst Cu(II) is regenerated on
aerial oxidation. The reaction between 1-iodoalkyne and 2-
aminopyridine also afforded the desired product in presence
of Cu(OAc)2 without I2 under the present reaction conditions.
In case of alkene, the reaction probably proceeds through the
formation of iodonium ion intermediate followed by coupling
with 2-aminopyridine through exocyclic amino group to afford
2-phenylimidazo[1,2-a]pyridine. Finally 3-iodoimidazo[1,2-
a]pyridine was obtained through the iodination of 2-
phenylimidazo[1,2-a]pyridine. The formation of two
regioisomers is possibly due to hard and soft nature of two
different nucleophilic centres of 2-aminopyridine.4f Although
the precise role of I2 is unknown for the coupling between 2-
aminopyridine and diarylalkyne, it is necessary for this
reaction. Probably the reaction proceeds through the Cu(III)
intermediate D.
Scheme 8 Proposed mechanism.
Conclusions
In summary, we have developed a regio-divergent method for
the synthesis of 2- and 3-iodoimidazo[1,2-a]pyridines through
a
copper-catalyzed oxidative coupling between 2-
aminopyridine and alkynes/alkenes in the presence of I2. This
versatile methodology is useful to attain the unsubstituted
imidazo[1,2-a]pyridines
and
2,3-diphenylimidazo[1,2-
a]pyridine. The current methodology is also applicable for the
synthesis of a new class of functionalized heterocycles, 2-iodo-
3-phenylbenzo[d]imidazo[2,1-b]thiazoles by the coupling of 2-
aminobenzothiazoles with alkynes. We believe the present
protocol would provide useful applications in organic,
medicinal and material chemistry.
Experimental Section
1H NMR spectra were determined on a 400 MHz and 300 MHz
spectrometers as solutions in CDCl3. Chemical shifts are
expressed in parts per million (δ) and are referenced to
tetramethylsilane (TMS) as internal standard and the signals
were reported as s (singlet), d (doublet), t (triplet), m
(multiplet) and coupling constants J were given in Hz. 13C NMR
spectra were recorded at 100 MHz and 75 MHz in CDCl3
solution. HRMS analysis was performed on a Q-TOF mass
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analyzer using the ESI ionization method. TLC was done on mixture petroleum ether and ethyl acetate (6:1) as an eluting
silica gel coated glass slide. Silica gel (60-120 mesh) was used solvent to afford the pure product.
for column chromatography. Petroleum ether refers to the Typical Experimental Procedure for 10: A mixture of 2-
fraction boiling in the range of 60-80 °C unless otherwise aminopyridine (1, 0.2 mmol) diarylacetylene (9, 0.2 mmol), and
mentioned. All solvents were dried and distilled before use. molecular iodine (0.2 mmol) was taken in oven dried 10 mL
Commercially available substrates were freshly distilled before round bottom flask in presence of Cu(OAc)2.H2O (10 mol%) in
the reaction. All reactions involving moisture sensitive 1,2-DCB (2 mL) and was stirred at 120 °C for 2.5 h under open
reactants were executed using oven dried glassware.
atmosphere. After completion of the reaction (TLC) the
reaction was cooled to room temperature and extracted with
Typical experimental procedure for 3: A mixture of 2- dichloromethane. The organic phase was dried over anhydrous
aminopyridine ( , 0.2 mmol), alkyne ( , 0.2 mmol) and Na2SO4. The crude residue was obtained after evaporating the
1
2
molecular iodine (0.2 mmol) was taken in an oven dried 10 mL solvent in vacuum and was purified by column
round bottom flask in presence of Cu(OAc)2.H2O (10 mol%) in chromatography on silica gel using a mixture petroleum ether
1,2-DCB (2 mL) and was stirred at 120 °C for 3 h under open and ethyl acetate (16:1) as an eluting solvent to afford the
atmosphere. After completion of the reaction (TLC) the pure product.
reaction was cooled to room temperature and extracted with
dichloromethane. The organic phase was dried over anhydrous
Acknowledgements
Na2SO4. The crude residue was obtained after evaporating the
solvent in vacuum and was purified by column
chromatography on silica gel using a mixture petroleum ether
and ethyl acetate (15:1) as an eluting solvent to afford the
A.H. acknowledges the financial support from from DST, GoWB
(Grant no. ST/P/S&T/4G-2/2014). S.S. thanks UGC-New Delhi (UGC-
JRF) and S.M. thanks CSIR-New Delhi (CSIR-JRF) for their
fellowships.
pure product. 2-Iodo-3-phenylimidazo[1,2-a]pyridine4
(3aa):
o
1
White solid (52 mg, 82%), mp: 139-141 C; H NMR (CDCl3, 400
MHz): δ 7.96 (d, J = 6.8 Hz, 1H), 7.51-7.37 (m, 6H), 7.10-7.06
(m, 1H), 6.66-6.63 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 146.7,
129.9, 129.1, 129.0, 128.2, 126.8, 124.8, 123.0, 117.0, 112.7,
93.6; HRMS calcd for C13H10IN2 [M +H]+: 320.9889; found
[M+H]+ : 320.9897.
Notes and references
1
2
3
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Typical Experimental Procedure for 5: A mixture of 2-
aminobenzothiozole (4, 0.2 mmol), alkyne (2, 0.2 mmol) and
molecular iodine (0.2 mmol) was taken in an oven dried 10 mL
round bottom flask in presence of Cu(OAc)2.H2O (10 mol%) in
1,2-DCB (2 mL) and was stirred at 120 °C for 2.5 h under open
atmosphere. After completion of the reaction (TLC) the
reaction was cooled to room temperature and extracted with
dichloromethane. The organic phase was dried over anhydrous
Na2SO4. The crude residue was obtained after evaporating the
solvent in vacuum and was purified by column
chromatography on silica gel using a mixture petroleum ether
and ethyl acetate (10:1) as an eluting solvent to afford the
pure product.
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Typical Experimental Procedure for 7: A mixture of 2-
aminopyridine (1, 0.2 mmol), styrene (6, 0.2 mmol) and
molecular iodine (0.3 mmol) was taken in an oven dried 10 mL
round bottom flask in presence of Cu(OAc)2.H2O (10 mol%) in
1,2-DCB (2 mL) and was stirred at 120 °C for 3 hours under
open atmosphere. After completion of the reaction (TLC) the
reaction was cooled to room temperature and extracted with
dichloromethane. The organic phase was dried over anhydrous
Na2SO4. The crude residue was obtained after evaporating the
solvent in vacuum and was purified by column
chromatography on silica gel using a mixture petroleum ether
and ethyl acetate (4:1) as an eluting solvent to afford the pure
product.
,
4
5
6
7
8
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Typical Experimental Procedure for 8: Solvent in vacuum and
was purified by column chromatography on silica gel using a
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11 Further information can be found in the CIF file. This crystal
was deposited in the Cambridge Crystallographic Data
Centre and assigned as CCDC 1474939 (for 3da), CCDC
1477441 (for 5aa) and CCDC 1474941 (for 7ba).
12 A. E. King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas and
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6 | J. Name., 2012, 00, 1-3
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