Switching of Regioselectivity in a Perfluorohexyl Iodide Mediated Synthesis of Phenylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/ejoc.201601586

3-Phenylimidazo[1,2-a]pyridines were synthesized through the perfluorohexyl iodide mediated coupling of 2-aminopyridines and phenylacetylenes. In situ iodination of the terminal alkyne by perfluorohexyl iodide reverses the polarity by generating a transient electrophilic iodoalkyne, and this alters the regioselectivity of the phenyl group. The reaction then proceeds by tandem electrophilic alkynylation and cyclization to form the fused-ring product. The protocol affords the 3-phenyl isomer with full regioselectivity and is complementary to reported methodologies for the synthesis of the 2-phenyl isomer starting from the same substrates.

Full text of DOI:10.1002/ejoc.201601586

A Journal of
Accepted Article
Title: Switching of Regioselectivity in a Perfluorohexyl Iodide-Mediated
Synthesis of Phenylimidazo[1,2-a]pyridines
Authors: Irwan Iskandar Roslan, Gaik-Khuan Chuah, and Stephan
Jaenicke
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601586
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601586
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601586
COMMUNICATION
Switching of Regioselectivity in a Perfluorohexyl Iodide-Mediated
Synthesis of Phenylimidazo[1,2-a]pyridines
a
a,
a,
Irwan Iskandar Roslan, Gaik-Khuan Chuah, * Stephan Jaenicke *
Abstract: An array of 3-phenylimidazo[1,2-a]pyridines has been
synthesized via perfluorohexyl iodide-mediated coupling of 2-
aminopyridines and phenylacetylenes. In-situ iodination of the
terminal alkyne by perfluorohexyl iodide reverses the polarity by
generating
a
transient electrophilic iodoalkyne, altering the
regioselectivity of the phenyl group. The reaction then proceeds via
a tandem electrophilic alkynylation and cyclization to form the fused
ring product. The protocol affords the 3-phenyl isomer with full
regioselectivity and is complementary to reported methodologies for
the synthesis of the 2-phenyl isomer starting from the same
substrates.
Introduction
The phenylimidazo[1,2-a]pyridine backbone can be found in
many pharmaceuticals, natural products, bioactive compounds,
biomolecules and agrochemicals.[1] For example, both the 2-
phenyl and 3-phenyl regioisomers are found in drugs and
bioactive compounds such as Zolpidem, Zolimidine, Miroprofen
and TP-003.[ The phenylimidazo[1,2-a]pyridine structural motif
has also been used in the field of material sciences[3] and NHCs
Scheme 1. Comparison between Lei’s, Das’s and Sheppard’s protocols with
our current work.
2]
situ which then transformed to the α-iodoacetophenone
intermediate via Au-catalyzed alkyne hydration before coupling
to 2-aminopyridine to form the desired product. Inspired by
Sheppard’s work on in-situ iodination of phenylacetylenes, we
hypothesized that if one employs a halogenating agent without
N-heterocyclic carbene).[4] With extensive potential of
(
applications, it is not surprising that phenylimidazo[1,2-
a]pyridines are attractive targets to synthesize.
Current protocols for the synthesis of 2-phenylimidazo[1,2-
a]pyridines include coupling of 2-aminopyridines with
I
the Au catalyst, the α-iodoacetophenone intermediate would not
[
5]
[6]
[7]
be formed. Instead, the in-situ halogenated phenylacetylene
moiety would couple directly to 2-aminopyridine to form the 3-
phenylimidazo[1,2-a]pyridine isomer (Scheme 1c). This is
possible as the in-situ halogenation of the phenylacetylene
nucleophile effects an “umpolung”, bestowing an electrophilic
character[14] of opposite reactivity upon the alkyne, thus
achieving a switch in regioselectivity via electrophilic alkynylation.
However, incorporating in-situ halogenation for tandem
cyclization reactions that include an electrophilic alkynylation is
challenging because the reaction conditions might not be
compatible with the cyclization and side reactions may take
place.[10b] Thus, it is not surprising that a one-step strategy for in-
situ halogenation of a terminal alkyne has rarely been reported
for the synthesis of heterocycles.[10b, 15] For the majority of these
protocols, the final product still contains the halogen, which is
not always desirable. Because of these complications, many
groups employ the umpolung alkyne as substrate instead.[16]
acetophenones,
nitroolefins,
propargylic
alcohols,
aldehydes,[ α,β unsaturated ketones and phenylacetylenes.
8]
[9]
[10]
Conversely, reported protocols for the synthesis of the 3-
regioisomer
typically
phenylacetaldehydes,
couple
2-aminopyridines
with
haloalkynes,[
11]
[12]
phenyl-acetones and
phenylacetophenones.[13] On seeing that the coupling partner
employed for the synthesis of the two phenyimidazo[1,2-
a]pyridine regioisomers are somewhat exclusive, we wanted to
investigate if there are any substrates that could be used to
synthesize both regioisomers, as this convenience would be
highly desirable.
Lei[10a] and Das[10b] independently reported a protocol for the
I
II
Ag -mediated
and
Co -catalyzed
synthesis
of
2-
phenylimidazo[1,2-a]pyridine via coupling of phenylacetylene
and 2-aminopyridines (Scheme 1a). Sheppard’s group
developed an alternative protocol to 2-phenylimidazo[1,2-
I
a]pyridine via a Au -catalyzed coupling of the same substrate
We have previously worked on in-situ α-bromination of 1,3-
system (Scheme 1b). In their work, N-iodosuccinimide (NIS) was
employed to generate an (iodoethynyl) benzene intermediate in-
dicarbonyls,[17] phenylacetones and phenylacetophenones
[13]
for
the synthesis of imidazo[1,2-a]pyridines using CBrCl
3
as the Br
source. We have also employed CBrCl and perfluorohexyl
3
iodide for the bromination and iodination of phenylacetylenes in
the electrophilic alkynylation of 1,3-dicarbonyls to form furans.[
Based on this, we tested the feasibility of in-situ halogenation of
[
a]
Department of Chemistry, National University of Singapore, 3
Science Drive 3, Singapore 117543.
18]
*
E-mail: chmsj@nus.edu.sg; chmcgk@nus.edu.sg
https://www.chemistry.nus.edu.sg/people/academic_staff/jaenicke.htm;
https://www.chemistry.nus.edu.sg/people/academic_staff/chuahgk.htm.
3
phenylacetylenes using CBrCl or perfluorohexyl iodide for the
cascade reactions to form the 3-phenylimidazo[1,2-a]pyridines.
However, due to the less acidic nature of the terminal alkyne
proton as compared to the α-protons in 1,3-dicarbonyls, slightly
harsher reaction conditions may be required for this protocol.
Supporting information for this article is available on the WWW
under http://dx.doi.org/xxxx
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European Journal of Organic Chemistry
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COMMUNICATION
Herein, we report the successful synthesis of 3-
Table 1. Optimization parameters for synthesis of 3-phenylimidazo[1,2-
a]pyridines.[a]
phenylimidazo[1,2-a]pyridines
via
in-situ
iodination
of
phenylacetylenes using perfluorohexyl iodide. This work
complements the protocols reported by groups of Lei, Das and
Sheppard for the synthesis of the 2-regioisomers. Starting with
the same substrate system of phenylacetylene and 2-
aminopyridine, it is now possible to obtain either the 2- or 3-
regioisomer of phenylimidazo[1,2-a]pyridines. In addition, the in-
situ halogenation of terminal alkynes to form 3-
phenylimidazo[1,2-a]pyridines is superior to methodologies
employing haloalkynes as substrates. Many of the haloalkynes
are not commercially available and have to be presynthesized.
Entry
Solvent
Base
Yield of
Yield of
[b],[c]
4a/4b[b] [%]
3a
[%]
1[d],[e]
2[e]
3
MeCN
MeCN
DMF
KHCO
KHCO
KHCO
KHCO
KHCO
KHCO
KHCO
KHCO
KHCO
-
33
51
7
3
3
3
3
3
3
3
3
3
Furthermore,
conjugated unsaturated haloalkynes
are
[
19]
lachrymatory compounds and many are highly toxic. Hence, it
is desirable to form the haloalkynes in-situ during reaction rather
than to synthesize and store them as substrates.
70 (59)
12
trace
16
10
5
4
NO
2
Me
38 (20)
38 (23)
63 (54)
0
5[e]
6[e]
7
DCE
Results and Discussion
EtOAc
We began our optimization studies by employing 0.5 mmol of
phenylacetylene 1a with 1.0 mmol of 2-amino-3-methylpyridine
dioxane
0
2
a, together with 1.0 mmol of KHCO
CBrCl in 3 mL MeCN under refluxing conditions for 16 h (Table
). Two main products were formed, including the desired 3-
phenylimidazo[1,2-a]pyridine 3a and the brominated derivative
a, which formed the major fraction (Table 1, entry 1).
3
as base and 1.25 mmol of
8
toluene
0
0
3
1
9[e]
MeCN/toluene
MeCN/toluene
MeCN/toluene
MeCN/toluene
MeCN/toluene
MeCN/toluene
MeCN/toluene
MeCN/toluene
79 (71)
0
trace
0
10[e]
4
Interestingly, switching to perfluorohexyl iodide resulted in a
strong preference for the formation of 3a over its iodinated
derivative 4b (Table 1, entry 2). No 2-phenylimidazo[1,2-
1 [
1
e]
KOAc
CO
NaHCO3
0
0
2[e]
1
K
2
3
70 (50)
45 (28)
90 (85)
41 (22)
10
12
trace
trace
0
a]pyridine was formed. In comparison,
a similar protocol
II
13[e]
involving the Cu -catalyzed coupling of phenylacetylene and 2-
aminopyridine with molecular iodine as the halogen source
formed 2-iodo-3-phenylimidazo[1,2-a]pyridine 4b as the main
product instead.[15a]
1 [
4
e]
CsHCO
CsHCO
CsHCO
3
3
3
15[e],[f]
The exclusive regioselectivity to 3a can be attributed to the
detection of only (iodoethynyl)benzene as intermediate in the
reaction mixture. This causes the umpolung reactivity of
phenylacetylene. No α-iodinated acetophenone intermediate[10b]
which gives rise to 2-regioisomer product was found. Various
solvents were also screened for their suitability in this protocol
1 [
6
e],[g]
0
[a]Reaction conditions: 1a (0.5 mmol), 2a (2.0 equiv), base (2 equiv),
halogenating agent (2.5 equiv) in 3 mL of solvent at 100 °C for 16 h. [b]Yield
(from GC) with respect to 1a. [c]Isolated yields in parenthesis. [d]Reaction
conducted using CBrCl
3
as the halogenating agent instead of
C
6
F13I.
[e]Reaction was conducted under reflux with [f]1.5 equiv of C
13I or [g]1.0 equiv
(
Table 1, entries 3 - 9). DMF was not suitable for this reaction,
with low yields of 3a and large amount of
iodoethynyl)benzene (Table 1, entry 3). Nitromethane and 1,2-
6
F
a
used.
(
dichloroethane produced slightly better yields of 3a but with a
poor ratio of 3a/4b compared to MeCN (Table 1, entries 2, 4 and
were tested. KOAc was not suitable for the reaction while K CO3
2
5). On the other hand, ethyl acetate gave a modest isolated yield
gave only a reduced yield of 50 % for 3a (Table 1, entries 11
of 3a at 54 % (Table 1, entry 6). In dioxane or toluene, no
reaction took place (Table 1, entries 7 and 8). Gratifyingly, a
mixed solvent system of MeCN/toluene of ratio 5:1 (v/v) gave an
and 12). Other bicarbonate salts were also screened including
NaHCO and CsHCO (Table 1, entries 13 and 14). Compared
3
3
with KHCO , CsHCO gave a significantly better yield of 85 %
3
3
improved yield of 71 % 3a with only traces of 4b formed (Table 1, whereas NaHCO3 gave poor results. Attempts to reduce the
entry 9).
amount of perfluorohexyl iodide from 2 to 1.5 and 1.0 equiv
caused a significant reduction in the yield of 3a (Table 1, entries
15 and 16). Thus, the optimized conditions employed for further
testing was 0.5 mmol of phenylacetylene 1a with 2 equiv of 2-
3
This mixed solvent system was subsequently employed to
screen for a suitable base (Table 1, entries 10 - 14). No reaction
occurred without a base, showing the importance of the base in
the reaction (Table 1, entry 10). Two additional potassium salts
amino-3-methylpyridine 2a, 1.0 mmol of CsHCO , 1.25 mmol of
perfluorohexyl iodide in
3 mL mixed solvent system of
MeCN/toluene 5:1 (v/v) under reflux for 16 h.
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European Journal of Organic Chemistry
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COMMUNICATION
Table 2. Scope of reaction.[a]
Next, a wide array of arylacetylenes was tested for their
compatibility under the optimized reaction condition (Table 2).
Good yields were obtained when a methyl group was at the
ortho, meta or para position (Table 2, 3b - 3d). Longer alkyl
substituents at the para position were also well tolerated,
including ethyl, n-butyl and tert-butyl (Table 2, 3e - 3g). Fluoro,
chloro, and bromo-substituted phenylacetylene also proceeded
with good to excellent yields (Table 2, 3h - 3j). An ester and
ethoxy moiety at the para position did not interfere with the
reaction and yields of 88 % and 71 %, respectively were
obtained (Table 2, 3k and 3l). Gratifyingly, other aromatic
derivatives of phenylacetylene, including naphthalene and
thiophene, coupled efficiently with 2-amino-3-methylpyridine 2a
as well, to form 3m and 3n with yields of 75 % and 79 %,
respectively. Unfortunately, 1-octyne was unreactive under the
reaction conditions (Table 2, 3o). This is not surprising as the
halogenation of terminal alkynes with CBrCl
3
and perfluorohexyl
iodide has only been reported for arylacetylenes.[
20]
Derivatives of 2-aminopyridine were also screened under the
optimized conditions. 75
% of 3p was formed when 2-
aminopyridine was employed. Methyl groups at the C-4 and C-5
position were well tolerated under the reaction conditions (Table
2
, 3q and 3r). It is interesting to see that with a methyl
substituent at the C-6 position, 3s was formed with a yield of
5 % yield. For the synthesis of 3-phenylimidazo[1,2-a]pyridines,
6
there has been many reports in the literature where the 6-methyl
substituted 2-aminopyridines reacted sluggishly or were
unreactive to their respective substrates.[
13, 16b, 21]
In addition, 2-
amino-5-chloro-3-picoline proceeded with a modest yield of 3t at
53 % albeit at a longer reaction time of 24 h.
Studies were conducted to better understand the mechanism
of the reaction. Firstly, as the (iodoethynyl)benzene has been
observed in some of the reaction mixtures during optimization
studies, we wanted to prove that iodination of the terminal
alkyne indeed occurs prior to coupling with the 2-aminopyridine
moiety. A reaction was done under the optimized conditions
using the iodoalkyne 5, 2 equiv of 2-amino-3-methylpyridine 2a
3
and 1 equiv of CsHCO without any addition of the halogenating
agent, perfluorohexyl iodide (Scheme 2a). 85 % of 3g was
obtained after 16 h which confirms that the reaction proceeds via
the iodoalkyne intermediate.
Next, we wanted to see if CsHCO or 2-aminopyridine is
3
responsible for deprotonation of phenylacetylene 1a prior to
iodination. 0.5 mmol of 1a was added to 3 mL MeCN/toluene 5:1
(
v/v) solvent mixture system with 1 equiv of CsHCO
3
and 2.5
of
iodoethynyl)benzene 6 was obtained after 8 h, showing that
equiv of perfluorohexyl iodide (Scheme 2b). 88
(
%
CsHCO
3
is involved in the deprotonation step. This is supported
(Table 1, entry
0). To check if the reaction proceeds via a radical pathway, 2.5
by the lack of reaction in the absence of CsHCO
1
3
equiv of 2,2,6,6-tetramethylpiperidin-1-yl oxyl (TEMPO) as
radical scavenger was added to the reaction mixture (Scheme
2c). After 16 h, only trace amounts of the desired product 3a
was formed, providing strong support that the reaction pathway
is radical in nature. This is similar to the findings of Sasson’s
group for in-situ halogenation of 1,3-dicarbonyls and terminal
arylaetylenes using perfluorohexyl iodide.[20a, 20b]
[a]Reaction conditions: 1 (0.5 mmol), 2 (2.0 equiv), CsHCO
3
6 13
(2 equiv), C F I
(2.5 equiv) in 3 mL MeCN/toluene 5:a (v/v) under reflux for 16 h. Isolated
yields reported. [b]Reaction time of 24 h.
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European Journal of Organic Chemistry
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COMMUNICATION
Conclusions
In summary, we have demonstrated a perfluorohexyl iodide-
mediated coupling of commercially available phenylacetylenes
and 2-aminopyridines to form 3-phenylimidazo[1,2-a]pyridines
through a series of cascade reactions that includes an initial
iodination of terminal alkyne moiety followed by electrophilic
alkynylation and cycloisomerization. The perfluorohexyl iodide
effectively iodinates the terminal alkyne, changing its reactivity.
This enables switching of the regioselectivity so that the 3-
regioisomer product is formed exclusively instead of the 2-
regioisomer. This protocol extends the scope of the
phenylacetylene/2-aminopyridine substrate system, selectively
forming either the 2- or the 3-regioisomer of phenylimidazo[1,2-
a]pyridine. Furthermore, the facile in-situ halogenation of
terminal alkynes under the reaction conditions offers a safer and
more convenient access to this class of heterocyclic compounds.
Experimental Section
Scheme 2. Mechanistic studies to determine the (a) reaction intermediate
Typical Procedure for the Formation of Imidazo[1,2-a]pyridines
(b) role of CsHCO
3
in the initial iodination step and (c) radical nature of
reaction.
A 25-mL round-bottomed flask was charged with phenylacetylene 1a
(
54.9 μL, 0.5 mmol), 2-amino-3-methylpyridine 2a (101 μL, 1.0 mmol),
CsHCO (194 mg, 1.0 mmol) and C 13I (270 μL, 1.25 mmol) in 3 mL of
MeCN/toluene 5:1 (v/v) solvent mixture. The reaction mixture was stirred
under reflux for 16 h. The mixture was then diluted with H O and
extracted with EtOAc (15 mL×5). The combined organic layer was
washed with brine and dried with anhydrous Na SO . After filtration, the
3
6
F
2
2
4
solvent was removed by rotary evaporation and the residue was purified
by column chromatography using hexane and ethyl acetate (v/v=2/1) as
eluent to afford 3a with 85 % yield.
8-Methyl-3-phenylimidazo[1,2-a]pyridine (3a):
1H NMR (300 MHz, CDCl
) δ 8.17 (d, J = 6.9 Hz, 1H), 7.66 (s, 1H), 7.56-
,42 (m, 4H), 7.37 (t, J = 7.1 Hz, 1H), 6.96 (d, J = 6.9 Hz, 1H), 6.68 (t, J =
.9 Hz, 1H), 2.63 (s, 3H); 13C NMR (300 MHz, CDCl
) δ 146.4, 131.7,
3
7
6
1
3
29.5, 129.0, 128.2, 128.0, 127.8, 126.0, 123.0, 121.1, 112.4, 16.9.
Figure 1. Plausible reaction mechanism
+
HRMS (ESI) calcd for C14
H N
13 2
[M+H] : 209.1073; found 209.1072..
Based on the results of the optimization experiments and
mechanistic studies, the formation of 3a is postulated to occur
as shown in Figure 1. The reaction begins with deprotonation of
phenylacetylene 1a to form the ionic salt A. The C-I bond in
perfluorohexyl iodide is homolytically cleaved to give C F13• and
6
I• radicals.[20a, 20b] Iodination of A by I• forms the iodoalkyne
Acknowledgements
Financial support from the Ministry of Education ARC Tier 1
Grant numbers R-143-000-603-112 and R-143-000-550-112 is
gratefully acknowledged.
intermediate B. This umpolung intermediate then undergoes an
electrophilic alkynylation reaction with 2-amino-3-methylpyridine
Keywords: alkynes • cyclization • regioselectivity • C-H
activation • synthetic methods
2
a to form C. Cycloisomerization of C yields intermediate D with
an acidic proton. This proton will be deprotonated by another
molecule of CsHCO to give the desired product 3a, releasing
O, CO and CsI salt.
3
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COMMUNICATION
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601586
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
A protocol for the synthesis of 3-
In-situ Bromination*
phenylimidazo[1,2-a]pyridines
perfluorohexyl iodide-mediated
coupling of 2-aminopyridines and
phenylacetylenes is reported,
proceeding via in-situ iodination of the
terminal alkyne. The iodination
reverses the polarity by generating a
transient electrophilic iodoalkyne,
altering the regioselectivity of the
phenyl group.
via
Irwan Iskandar Roslan, Gaik-Khuan
Chuah* and Stephan Jaenicke*
Page No. – Page No.
Switching of regioselectivity in a
perfluorohexyl iodide-mediated
synthesis of phenylimidazo[1,2-
a]pyridines
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.