molecules
Article
Investigation of the Pyridinium Ylide—Alkyne
Cycloaddition as a Fluorogenic Coupling Reaction
Simon Bonte 1 , Ioana Otilia Ghinea 2 , Rodica Dinica 2 , Isabelle Baussanne 1, * and
Martine Demeunynck 1, *
1
2
*
Department of Pharmacochemistry, Université Grenoble Alpes, CNRS, DPM UMR 5063, F-38041 Grenoble,
France; [email protected]
Department of Chemistry, Physics and Environment, Faculty of Science and Environment,
“Dunarea de Jos” University of Galati, 111 Domneasca Street, 800201 Galati, Romania;
[email protected] (I.O.G.); [email protected] (R.D.)
Correspondence: [email protected] (I.B.);
[email protected] (M.D.); Tel.: +33-476-635-314 (M.D.)
Academic Editor: Philippe Belmont
Received: 26 January 2016 ; Accepted: 4 March 2016 ; Published: 10 March 2016
Abstract: The cycloaddition of pyridinium ylides with alkynes was investigated under mild
conditions. A series of 13 pyridinium salts was prepared by alkylation of 4-substituted pyridines.
Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures,
solvents, added bases) was studied, and 11 indolizines, with three points of structural variation, were,
thus, isolated and characterized. The highest yields were obtained when electron-withdrawing groups
were present on both the pyridinium ylide, generated in situ from the corresponding pyridinium salt,
and the alkyne (X, Z = ester, amide, CN, carbonyl, etc.). Electron-withdrawing substituents, lowering
the acid dissociation constant (pKa) of the pyridinium salts, allow the cycloaddition to proceed at
pH 7.5 in aqueous buffers at room temperature.
Keywords: indolizine; coupling reaction; ylide; dipolar cycloaddition
1. Introduction
We have been interested in the indolizine chemistry for several years. Indolizine is a
nitrogen-containing bicyclic heterocycle, and its derivatives display interesting biological [1–5] and
optical properties [6–13] (fluorescence and circular dichroism [14,15]). Indolizines have been used as
biomarkers [16] and in the fluorescent labeling of carbon nanotubes [17] and graphene [18], for instance.
Among the main routes of preparation that have been designed, we can cite the metal-catalyzed
cyclization of 2-alkynylpyridines [19–25] or 2-pyridine alkynyl carbinols [26–31]. The most common
metal-free methodology [2,32,33] involves the 1,3-dipolar cycloaddition of pyridinium ylides with
alkynes (Scheme 1) [2,34–39]. The dihydroindolizines thus formed spontaneously, aromatize under
air oxidation. This chemistry has been the subject of a large number of publications, focusing, in
particular, on the formation and reactivity of the ylides [34,35,40–44] and on the mechanism of the
cycloaddition [33]. More recently, improvements in the reaction conditions have been reported,
by using oxidant-free cycloaddition to alkenes [32], one-pot [38], microwave-activated [34,35], or
biocatalyzed processes [36]. Note that most of the work reported so far in the literature involved
N-benzoylmethylpyridinium-derived ylides [45,46]. The purpose of the present work was to explore
the potency of the pyridinium ylide-alkyne cycloaddition as a click–type coupling reaction.
Molecules 2016, 21, 332; doi:10.3390/molecules21030332
www.mdpi.com/journal/molecules
achieve this goal, we modified the structure of the ylide precursors: reactive or easily modified
substituents were introduced on the pyridinium salts (R1 group in Scheme 1) and ester or amide
groups were used to stabilize the ylide (R2 = RO- or RNH-, in Scheme 1) in place of the benzoyl group
usually reported in the literature. The structure optimization of the reactants allowed the cycloaddition
to proceed
at 332
room temperature in very mild conditions including pH 7.5 aqueous buffers, yielding
Molecules
2016, 21,
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indolizines with three possible points of functionalization.
R1
R1
R1
R1
base
N
R2
X
R3
O
R1
-HR3
CO2Et
N
R2
N
R3
R2
O
R3
O
R3
N
R2
O
CO2Et
or
atm. O2
N
CO2Et
R2
O
Ylide formation
Scheme 1.
1. General
Scheme
General mechanism.
mechanism.
2. Results
The key points to investigate were the effectiveness of this cycloaddition in mild conditions (room
temperature,
neutral
near neutral conditions),
easeSalt
of accessibility of the reactants, and their practical
2.1. Preparation
and or
Characterization
of the Pyridinium
pre- or post-functionalization. For all these reasons, we decided to prepare a series of ylide precursors
We first prepared a series of 13 pyridinium salts. To keep the symmetry of the starting molecule
(pyridinium salts) and to compare their reactivity in the presence of alkynes in various conditions.
and to prevent formation of regioisomers after cycloaddition, substituents were only introduced at
We first aimed to select the best partners for the application as coupling methodology. To achieve this
position 4 of the pyridine ring [37].
goal, we modified the structure of the ylide precursors: reactive or easily modified substituents were
The pyridinium salts were obtained by alkylation of the pyridine derivatives with methyl
introduced on the pyridinium salts (R1 group in Scheme 1) and ester or amide groups were used to
2-bromoacetate (compounds 1–7), 2-iodoacetophenone derivatives (compounds 8 and 9), or 2-bromostabilize
the ylide (R2(compound
= RO- or RNH-,
in Scheme
1) in
place of the
benzoylIngroup
usually
reported
N-propylacetamide
10) in acetone
under
ultrasound
activation.
the case
of alkylation
in with
the literature.
The structure optimization
of the
reactantssalts
allowed
the cycloaddition
to proceed
diethyl 2-iodomalonate
to prepare the
pyridinium
containing
two carboxylic
esters at
room
temperature
in
very
mild
conditions
including
pH
7.5
aqueous
buffers,
yielding
indolizines
with
(compounds 11–13, R3 = CO2Et), very low yields were observed under these conditions. The reaction
three
points
of functionalization.
waspossible
improved
by using
the diethyl 2-iodomalonate in large excess. The structures, yields, pKa and
1H-NMR data are collected in Table 1.
2. Results
As previously observed [47,48], the electronic nature of the substituent present at position 4
modulates the pKa values, and the pKa variation correlates well with the Hammett constant of the
2.1. Preparation and Characterization of the Pyridinium Salt
R1 group. The electron-withdrawing groups decrease the pKa values (compare 4–7 versus 1). This
We was
first more
prepared
a series of
13 pyridinium
salts.orToCOCH
keep 3the
symmetry
of the
molecule
) than
inductive
(CF3starting
) withdrawing
effect
pronounced
with
mesomeric (CN
substituents.
effect ofofthe
nature of R1 after
has been
studied [49] substituents
and seemed more
for the at
and
to preventThe
formation
regioisomers
cycloaddition,
wereprominent
only introduced
phenacyl
[47],ring
however
position
4 ofanalogues
the pyridine
[37]. the measurements were made in different conditions (ylides
dissolved
in methanol).
In another
study, theby
deprotonation
of the
pyridinium
salts
was studied
by NMR
The pyridinium
salts
were obtained
alkylation of
pyridine
derivatives
with
methyl
in
DMSO
in
the
presence
of
a
strong
base
[48].
The
authors
found
that
the
effect
on
the
deprotonation
2-bromoacetate (compounds 1–7), 2-iodoacetophenone derivatives (compounds 8 and 9), or
of the ring substituents was greater
than the
of the methylene
substituent.
2-bromo-N-propylacetamide
(compound
10)effect
in acetone
under ultrasound
activation. In the case of
The
proton
NMR
spectra
of
4-substituted
pyridinium
salts
are
characterized
downfield
by two
alkylation with diethyl 2-iodomalonate to prepare the pyridinium salts
containing two
carboxylic
esters
multiplets
for
H-2/H-6
and
H-3/H-5,
the
latter
being
more
shielded,
and
a
singlet
for
the
CH
2 generally
(compounds 11–13, R3 = CO2 Et), very low yields were observed under these conditions. The reaction
found between 4.4 and 6.6 ppm. The correlation between the presence of the electron-withdrawing
was improved by using the diethyl 2-iodomalonate in large excess. The structures, yields, pKa and
group R1 and pKa (deprotonation and ylide formation) is reflected by higher δ value for the CH2 signal.
1 H-NMR
data are collected in Table 1.
The integration of this singlet was lower than expected with compounds 4–6 and this signal may also
As previously observed [47,48], the electronic nature of the substituent present at position 4
be lacking (see 11 and 12) probably due to high H/D exchange rate in CD3OD. We observed in the
modulates the pKa values, and the pKa variation correlates well with the Hammett constant of the
spectrum of the 4-acetylpyridinium salt 6 in CD3OD, the presence of a second set of shielded signals,
R1 group. The electron-withdrawing groups decrease the pKa values (compare 4–7 versus 1). This
not found in DMSO-d6, which was attributed to the formation of hemiketal or ketal derivatives in this
effect
wasand
more
with
mesomeric
(CN or(the
COCH
inductive
3 ) than
3 ) withdrawing
solvent
thatpronounced
increased with
time
spent in solution
simulated
spectra
of the(CF
different
species
substituents.
The
effect
of
the
nature
of
R
has
been
studied
[49]
and
seemed
more
prominent for
1
were in agreement with the experimental data).
the phenacyl analogues [47], however the measurements were made in different conditions (ylides
dissolved in methanol). In another study, the deprotonation of pyridinium salts was studied by NMR
in DMSO in the presence of a strong base [48]. The authors found that the effect on the deprotonation
of the ring substituents was greater than the effect of the methylene substituent.
The proton NMR spectra of 4-substituted pyridinium salts are characterized downfield by two
multiplets for H-2/H-6 and H-3/H-5, the latter being more shielded, and a singlet for the CH2 generally
found between 4.4 and 6.6 ppm. The correlation between the presence of the electron-withdrawing
group R1 and pKa (deprotonation and ylide formation) is reflected by higher δ value for the CH2
signal. The integration of this singlet was lower than expected with compounds 4–6 and this signal
may also be lacking (see 11 and 12) probably due to high H/D exchange rate in CD3 OD. We observed
in the spectrum of the 4-acetylpyridinium salt 6 in CD3 OD, the presence of a second set of shielded
signals, not found in DMSO-d6 , which was attributed to the formation of hemiketal or ketal derivatives
Molecules 2016, 21, 332
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in this solvent and that increased with time spent in solution (the simulated spectra of the different
species were in agreement with the experimental data).
Molecules 2016, 21, 332
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Table 1. Structures, yields, pKa values, and proton NMR data of the pyridinium salts.
Table 1. Structures, yields, pKa values, and proton NMR data of the pyridinium salts.
R1
N
R2
XR3
O
X = Br, Cl, I
Salt
Salt
R1
1
2
H 3
NH24
5
NHAc6
CF3 7
8
CONHPr
9
COCH
103
CN11
12
CN13
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
R2
R2
R3
H
OMe
NH2
OMe
OMe
H
NHAc
OMe
CF3
OMe
OMe
H
CONHPr
OMe
OMe
H
COCH3
OMe
OMe
H
CN
OMe
CN
PhH
OMe
CN
Ph-NO2
OMe
CN
NHCH
3 H7
H
OEt
OMe
H
COCH3
OEt
Ph
H
CN
OEt
R3
Yields
H%
H
H71
H83
H
H81
H54
H80
H
H64
CO260
Et
CO2 Et
70
CO2 Et
1
YieldsR%
Hammett
71
Cste
83
81 0
54
−0.66
80
640.06
600.54
700.36
60
600.50
890.66
R1 Hammett
pKa a
1H-NMR
Cstea
pKa
0
´0.66
8.30
0.06
0.54
8.84
0.36
8.74
0.50
8.25
0.66
δ H2/H6
8.30
8.84
9.01
8.74
8.25
8.09
8.24
8.74
8.04
9.39
8.16
8.11
9.19
7.07
9.35
nd
5.51
9.29
5.04
9.30
nd c
b
1 H-NMR b
1
1 H-NMR b
1 H-NMR b
1H-NMR b
H-NMR b δ H3/H5
δ H2/H6
δ CH2 /CH
δ H3/H5
9.01
8.09
8.748.23
9.396.92
9.19
9.358.14
9.298.66
9.308.52
9.26
9.248.63
9.208.64
9.36
8.85
9.44
δ
8.23
6.92
8.14
8.66
8.52
8.63
8.64
8.85
8.83
8.59
8.28
8.61
8.66
CH2/CH5.66
5.12
5.66 5.51
5.12 5.83
5.75
5.51 5.88
5.83 5.75
8.24
5.75 6.61
6.60
8.04
5.88 5.60
8.16
5.75 Not obs.
99
Not obs.
8.11
6.61 Not
40
obs.
H
60
7.07
9.26
8.83
6.60
CN a
Ph-NO2
The pKa values were determined by potentiometry of 10´3 M solution of the salt in 0.1 M NaClO4 . The
H
60
nd were recorded
9.24 in CD OD;
8.59
5.60 data.
CN measurements
NHC3H7 were made
b The NMR spectra
c Non-reproducible
in triplicate;
3
89
5.51
9.20
8.28
Not obs.
H
OEt
CO2Et
OEt
CO2Et
99
5.04
9.36
8.61
Not obs.
COCH3
2.2. Reactivity Studies
40
nd c
9.44
8.66
Not obs.
CN
OEt
CO2Et
The
reactivity
of the different
salts withofalkynes
was compared
using
reference
reaction:
The pKa
values
were determined
by potentiometry
10−3 M solution
of the salt in
0.1 Ma NaClO
4.
b
c
Themethanol
measurements
were made
in triplicate;
The NMR
spectra were recorded
in 3CD
was chosen
as solvent,
ethyl propiolate
as dipolarophile,
and K2 CO
for3OD;
ylide generation.
Non-reproducible
data.
The reaction mixtures
were stirred at 25 ˝ C for 18 h, and the indolizines were isolated. The ease of
a
isolation and purification is an important point for the usefulness of the reaction. Therefore, in the
2.2. Reactivity
Studies
following
tables, we give and discuss the yields of isolated indolizines.
As known
literature,
thewith
cycloaddition
is fully
regioselective,
ethyl and
methyl esters
The reactivity
of in
thethe
different
salts
alkynes was
compared
using athe
reference
reaction:
being
in as
positions
and 3,propiolate
respectively,
in our study and
easily
identified.
methanol
wasfound
chosen
solvent,1 ethyl
as dipolarophile,
and
K2CO
3 for ylide generation.
The reaction mixtures were stirred at 25 °C for 18 h, and the indolizines were isolated. The ease of
2.2.1. Influence of the R1 Substituent
isolation and purification is an important point for the usefulness of the reaction. Therefore, in the
We first
importance
of the
nature of
R1 on the reactivity (Table 2). Introduction of
following tables,
we studied
give andthe
discuss
the yields
of isolated
indolizines.
groups
on the pyridine
ringregioselective,
clearly favoredthe
theethyl
cycloaddition.
Aselectron-withdrawing
known in the literature,
the cycloaddition
is fully
and methylHigher
esters yields
(77% and
81%) were
obtained
in the presence
electron-withdrawing
mesomeric groups (COCH3 or
being found
in positions
1 and
3, respectively,
in ourof
study
and easily identified.
CN, respectively) that efficiently stabilize the negative charge of the ylides by delocalization. In the
2.2.1. Influence
of the
1 Substituent
case of the
CF3Rsubstituent
(entry 6), the NMR data showed the presence of the desired indolizine 19
and of the corresponding dimethyl carboxylate, formed by trans-esterification of the ethyl ester at
We first studied the importance of the nature of R1 on the reactivity (Table 2). Introduction of
position 1 by methanol. To selectively prepare 19, the reaction should be performed in ethanol or in a
electron-withdrawing groups on the pyridine ring clearly favored the cycloaddition. Higher yields
non-nucleophilic solvent such as DMF (cf. part 2.2.2). Under these mild conditions, the 4-amino or
(77% and 81%) were obtained in the presence of electron-withdrawing mesomeric groups (COCH3 or
amido-substituted pyridinium salts (entries 2 and 3), which display the lowest Hammett constant, did
CN, respectively) that efficiently stabilize the negative charge of the ylides by delocalization. In the
not react.
case of the CF3 substituent (entry 6), the NMR data showed the presence of the desired indolizine 19
and of the corresponding dimethyl carboxylate, formed by trans-esterification of the ethyl ester at
position 1 by methanol. To selectively prepare 19, the reaction should be performed in ethanol or in
a non-nucleophilic solvent such as DMF (cf. part 2.2.2). Under these mild conditions, the 4-amino or
amido-substituted pyridinium salts (entries 2 and 3), which display the lowest Hammett constant,
did not react.
From these experiments, compounds 6 and 7 were selected for further studies.
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Molecules 2016, 21, 332
Molecules 2016, 21, 332
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4 of 15
Table 2. Influence of the pyridine substituent R on the yields of indolizines a .
Table 2. Influence of the pyridine substituent R11 on the yields of indolizines a.
Table 2. Influence of the pyridine substituent R1 on the yields of indolizines a.
Hammett
Entry Pyridinium Salt
R1
Hammett
Constant Indolizine Yield (%)
Yield
(%)
Entry Pyridinium
Pyridinium
R1 Hammett Constant Indolizine
Entry
SaltSalt R
Indolizine
Yield
Constant
1
H1
14
1
0
59 (%)
H2 H
14
00
14 15
5959
21 1
NH
21 1
−0.66
0
2
NH
15
2 NH2
2
−0.66
0
2
2
´0.66
15
00
3
NHAc
16
3
0.06
3
3
NHAc
0.06
16
0
NHAc
16
0.06
0
53
CONHPr
17
43
0.36
66
4
5
CONHPr
0.36
17 17
6666
5
CONHPr
4
0.36
6 6
COCH
3
5 5
0.50
COCH
0.50
18 18
7777
3
COCH
18
0.50
77
b b
46 4
CF3 3CF3
65 6
0.54
0.54
19 19
5555
b
4
CF
19
3 CN
6
0.54
55
7
7
0.66
20
81
7
CN
20
7
0.66
81
7 eq.)and
CN
20
0.66
81
a The7pyridinium salts
a The
ethyl
propiolate
(1.5 eq.)
in MeOH.
was
then
2 CO3 (1 eq.)
pyridinium salts (1(1eq.)
and
ethyl
propiolate
(1.5were
eq.)dissolved
were dissolved
inKMeOH.
K2CO
3 (1
eq.)
b
a The
added
to generate salts
andand
the resulting
solutions were
stirred
18h at
room temperature.
of eq.)
19
pyridinium
(1 eq.)
propiolate
eq.) were
dissolved
in MeOH.
K2COat3 (1
was
then
added the
to ylides
generate
the ethyl
ylides
and the (1.5
resulting
solutions
were
stirred Mixtures
18h
room
and
of
the
corresponding
1,3-dimethyl
carboxylate
analogue
were
obtained
in
a
non-reproducible
ratio.
was
then
added
to
generate
the
ylides
and
the
resulting
solutions
were
stirred
18h
at
room
b
temperature. Mixtures of 19 and of the corresponding 1,3-dimethyl carboxylate analogue were
b Mixtures of 19 and of the corresponding 1,3-dimethyl carboxylate analogue were
temperature.
obtained
in a non-reproducible
ratio.
From these
compounds
6 and 7 were selected for further studies.
obtained
in aexperiments,
non-reproducible
ratio.
2.2.2. Influence of the Solvent and of the Nature of the Added Base
2.2.2. Influence
Influence of
of the
the Solvent
Solvent and
and of
of the
the Nature
Nature of
of the
the Added
Added Base
2.2.2.
Base
To evaluate the importance of the solvent on the cycloaddition efficiency, the reactions were
To evaluate
the importance
importance of
of the solvent
solvent on
on the
the cycloaddition
cycloaddition efficiency,
efficiency, the
the reactions
reactions were
were
To
evaluate
the
performed
in parallel
in DMF, a polarthe
non-nucleophilic
solvent, and methanol.
Three bases,
NH4OH,
performed
in
parallel
in
DMF,
a
polar
non-nucleophilic
solvent,
and
methanol.
Three
bases,
NH
OH,
performed
in parallel in DMF, a polar non-nucleophilic solvent, and methanol. Three bases, NH44OH,
NEt
3, and K2CO3 were also tested. The data are collected in Table 3.
NEt
,
and
K
CO
were
also
tested.
The
data
are
collected
in
Table
3.
NEt33, and K22CO33were also tested. The data are collected in Table 3.
Table 3. Influence of the nature of the solvent and of the base on the yields of indolizines 18 and 20
Table 3.
of the
nature
of the solvent and of the base on the yields of indolizines 18 and 20
Table
3. Influence
Influencesalts
of
the
nature
from
pyridinium
6 and
7. of the solvent and of the base on the yields of indolizines 18 and 20
from pyridinium salts 6 and 7.
from pyridinium salts 6 and 7.
Entry
Entry
Entry
1
21 1
2
32 3
43 4
5
54 6
5
6 7
76 8
9
87 10
98 11
9 12
10
13
10
11 14
11
12
15
12
13
13
14
14
15
15
R1
Base (1 eq.)
Solvent
Base (1
Solvent
R 1 3 R1
Base
(1eq.)
eq.)
Solvent
COCH
K2CO
3
MeOH
COCH
K
CO
MeOH
COCH33
K222CO
CO333
MeOH
3
COCH
K
MeOH
COCH3
K2 CO3
MeOH
COCH
3
K
2CO3
MeOH
COCHCOCH
3
NH
OH
NH44OH
MeOHMeOH
3
COCH
3
NH
4OH
MeOH
COCH
NEt
MeOH
3
COCH3
NEt33
MeOH
COCH
KNEt
DMF MeOH
3
2 CO3
COCH
3
COCH
3
K
2CO3
DMF
COCH3
NH4 OH
DMF
COCH
3
KNEt
2CO3
DMF
COCH
3
NH
4
OH
DMF
COCH
DMF
3
3
COCH
3
NH
4OH
DMF
COCH
KNEt
DMF DMF
3
2 CO
COCH
3
33
COCH
NH
DMF DMF
3
4 OH
COCH
3
NEt
3
COCHCOCH
3
KNEt
2CO3
DMF DMF
3
3
COCH33CN
K22CO
CO
3
DMF
K
MeOH DMF
COCH
NH
4OH
3
K
CO
MeOH
COCH
3CN
NH
4
OH
DMF
2
COCH3
NEt
33
DMF
CN
KNEt
DMF DMF
2 CO33
COCH
CN 3CN
K
2
CO
3
MeOH
K2 CO3
MeOH
CN
K
2CO
MeOH
pH
7.5 33
CN
K
2CO
MeOH
CN
Phosphate
H2 O MeOH
CN
K
2CO3
CN
K
2CO3
DMF
buffer
CN
K22CO
CO33
DMF
CN
K
MeOH
CN
K
2CO3
MeOH
CN
pH 7.5 Phosphate buffer
H2O
CN
pH 7.5 Phosphate buffer
H2O
T °C
25
25 25
25
25
25
25 25
25
25 25
25 25
25
25
25
25 25
25
25 25
25 25
25 25
25
25 25
25 25
25
25 25
40 25
25
25
25 25
25
25
40
40
25
25
T ˝T
C °C
Time (h)
Time (h)
Time
1 (h)
11
18
18
18
11
111
1
111
1
11
115
5
515
555
18
55
5
55
18
5
18
18
18
5
5
18
18
18
18
Yield (%)
Yield (%)
(%)
Yield
50
50
50
77
77
77
45
45
45
38
38
88
38
88
44
88
44
45
44
>90
45
48
45
>90
48
>90
45
48
81
48
48
70
48
45
38
45
81
24
81
70
70
38
38
24
24
Molecules 2016,
2016, 21,
21, 332
332
Molecules
5 of 15
K2CO3 appeared as the most efficient base in both solvents (entries 1 and 5), and DMF emerged
appeared
as the most
efficient
both solvents (entries 1 and 5), and DMF emerged
2 CO3choice
as theKbest
to perform
reactions
withbase
6 (Rin
1 = COCH3). The reaction proceeded quickly in this
as
the
best
choice
to
perform
reactions
with
6
(R
=
COCH3 ).the
The
reaction
proceeded
quickly
in this
solvent with good yield obtained in 1 h (entry 5).1Increasing
reaction
time
to 5 h (entry
8) did
not
solvent
with
good
yield
obtained
in
1
h
(entry
5).
Increasing
the
reaction
time
to
5
h
(entry
8)
significantly improve the yield. This solvent effect was also observed with the 4-cyano analog 7, did
for
not significantly
improve
yield. This solvent
effectthe
wasreaction
also observed
with
the 4-cyano
which
both solvents
may the
be alternatively
used. Still,
remained
faster
in DMFanalog
than in7,
for which (compare
both solvents
may11beand
alternatively
used. Still,
theattempted
reaction remained
faster
in DMF than
methanol
entries
13). The reaction
was
at a higher
temperature
in
in methanol
(compare
11leading
and 13).
reaction was
attempted atincluding
a higher temperature
in
methanol
(entries
12 andentries
14), but
to The
the formation
of side-products
those resulting
methanol
(entries
12
and
14),
but
leading
to
the
formation
of
side-products
including
those
resulting
from trans-esterification.
fromThe
trans-esterification.
reaction was also performed in pH 7.5 phosphate buffer (entry 15). The pyridinium salt 7
The
reaction
was also
performed
pHhydrophobic
7.5 phosphate
bufferof(entry
15). The
pyridinium
7 was
was soluble
in aqueous
solution,
butin
the
nature
the ethyl
propiolate
wassalt
a severe
soluble
in
aqueous
solution,
but
the
hydrophobic
nature
of
the
ethyl
propiolate
was
a
severe
limitation.
limitation. Nevertheless, we were thrilled to isolate the resulting indolizine 20 in 24% yield. This
Nevertheless,
wethat
were
isolate
the resulting
indolizine
20 in
24%the
yield.
Thisformation
result indicated
result
indicated
thethrilled
pKa oftothe
salt (8.16
for 7) was
compatible
with
partial
of the
that
the
pKa
of
the
salt
(8.16
for
7)
was
compatible
with
the
partial
formation
of
the
ylide
ylide under these conditions, thus allowing the cycloaddition reaction. It should be noted under
that, tothese
our
conditions,
thus
allowing
the
cycloaddition
reaction.
It
should
be
noted
that,
to
our
knowledge,
dipolar
knowledge, dipolar cycloaddition involving a pyridinium ylide in neutral aqueous solution has not
cycloaddition
involving
a pyridinium ylide in neutral aqueous solution has not been reported so far.
been
reported so
far.
In
an
effort
to
increase
the reactivity
reactivity in
in water,
water, the
the reaction
reaction was
was performed
performed with
with compounds
compounds
In an effort to increase the
11–13 that
that displayed
displayed lower
lower pKa
pKa values
values and
and would
would mainly
mainly exist
exist as
as ylides
ylides at
at pH
pH 7.5.
7.5. The
Thereactions
reactionswere
were
11–13
˝ C in Tris
performed
in
pH
7.5
buffer
solutions.
For
solubility
reasons,
the
first
attempts
were
made
at
40
performed in pH 7.5 buffer solutions. For solubility reasons, the first attempts were made at 40 °C in
buffer.
As indicated
in Table
the cyclization
was highly
on the nature
of the
substituent
Tris
buffer.
As indicated
in 4,
Table
4, the cyclization
wasdependent
highly dependent
on the
nature
of the
at
position
4.
There
was
no
reaction
with
the
unsubstituted
pyridinium
11
(entry
1),
and
a
low
substituent at position 4. There was no reaction with the unsubstituted pyridinium 11 (entry 1),yield
and
indolizine
obtained22from
4-acetyl from
pyridinium
12 (entry
2). The 4-cyanopyridinium
13
ain low
yield 22
in was
indolizine
wasthe
obtained
the 4-acetyl
pyridinium
12 (entry 2). The
yielded the indolizine
in a reasonable
40% yield.
we had previously
observed
negative
effect
4-cyanopyridinium
13 23
yielded
the indolizine
23 in As
a reasonable
40% yield.
As we ahad
previously
˝ C under vigorous stirring and, as a
of
temperature
on
yields,
the
reaction
was
then
performed
at
25
observed a negative effect of temperature on yields, the reaction was then performed at 25 °C under
result, thestirring
yield jumped
(entry
Replacing
buffer
with 4).
phosphate
buffer
had
vigorous
and, astoa 63%
result,
the 4).
yield
jumpedTris
to 63%
(entry
Replacing
Tris(entry
buffer5)with
a negative buffer
effect on
the 5)
yield
dropped
to 42%.
Foryield
comparison,
the reactivity
of 13
in organic
phosphate
(entry
hadthat
a negative
effect
on the
that dropped
to 42%. For
comparison,
solvents
was
investigated
(entries
6
and
7).
A
very
strong
solvent
effect
was
observed.
While
no
the reactivity of 13 in organic solvents was investigated (entries 6 and 7). A very strong solvent
effect
formation
of
23
occurred
in
methanol,
it
was
isolated
in
excellent
yield
in
DMF.
The
difference
in
was observed. While no formation of 23 occurred in methanol, it was isolated in excellent yield in
reactivity
12in
and
13 in Tris
buffer may
be 13
due
thebuffer
unfavorable
the hydrate
DMF.
The between
difference
reactivity
between
12 and
intoTris
may beformation
due to theofunfavorable
form
of
12.
However,
these
first
data
confirmed
the
feasibility
of
this
dipolar
cycloaddition
in aqueous
formation of the hydrate form of 12. However, these first data confirmed the feasibility of this
dipolar
solutions
starting
with
4-cyanopyridinium
salts
7
and
13.
cycloaddition in aqueous solutions starting with 4-cyanopyridinium salts 7 and 13.
Table 4. Formation of indolizine from diethyl dicarboxylate substituted pyridinium 11–13 in pH 7.5
Table 4. Formation of indolizine from diethyl dicarboxylate substituted pyridinium 11–13 in pH 7.5
buffer solutions.
buffer solutions.
Base
Solvent
C
Indolizine Yield
(%) (%)
EntryEntry R1 R1
Base
Solvent TT˝°C
Indolizine
Yield
1
H
pH
7.5
Tris
buffer
H
O
40
21
0
21
1
H
pH 7.5 Tris buffer
H
40
0
2 2O
COCH3
Tris buffer
H2 O
40
22
12
22
2 2 COCH
3
pH pH
7.57.5
Tris
buffer
H2O
40
12
3
CN
pH 7.5 Tris buffer
H2 O
40
23
40
3 4 CN CN
pH pH
7.57.5
Tris
2O
40
Trisbuffer
buffer
HH
25
2323
63 40
2O
5
CN
pH
7.5
phosphate
buffer
H
O
25
23
42
23
2 2O
4
CN
pH 7.5 Tris buffer
H
25
63
6
CN
K2 CO3
MeOH
25
23
0
23
5 7 CN CN pH 7.5 phosphate
buffer
H
2O
25
42
K2 CO3
DMF
25
23
93
23
6
CN
K2CO3
MeOH
25
0
The mixtures of pyridinium salts (1 eq.) and ethyl propiolate (1.5 eq.) were stirred at the chosen temperatures
23
CNare given as yieldsKof2CO
3
25
93
for718 h. Results
isolated
indolizines. DMF
The mixtures of pyridinium salts (1 eq.) and ethyl propiolate (1.5 eq.) were stirred at the chosen
temperatures for 18 h. Results are given as yields of isolated indolizines.
Molecules 2016, 21, 332
6 of 15
Molecules 2016, 21, 332
6 of 15
2.2.3. Effect
Effect of
of the
the R
R22Group
Group
2.2.3.
To extend
extend the
the scope
scope of
of the
the reaction,
reaction, it
it was
was also
also important
important to
to compare
compare the
the reactivity
reactivity of
of pyridinium
pyridinium
To
salts
containing
various
methylene
R
substituents.
As
shown
in
Table
5,
the
yield
in
7-cyanoindolizine
salts containing various methylene R22 substituents. As shown in Table 5, the yield in 7-cyanoindolizine
was higher
higherstarting
starting
from
the methyl ester 7 than from benzoyl derivatives 8 or 9. The presence
of
was
from
the
Molecules
2016,
21,the
332 methyl ester 7 than from benzoyl derivatives 8 or 9. The presence
6 of
of 15
Molecules
2016,2016,
21, 332
6 of 15
Molecules
21, 332
6 of 15
Molecules
2016,
21,
66 of
Moleculeson
2016,the
21, 332
332
of 15
15 yield
the
nitro
group
phenyl
ring,
lowering
the
pH
of
ylide
formation,
slightly
increased
the
nitro group on the phenyl ring, lowering the pH of ylide formation, slightly increased the yield
2.2.3.
Effect
of
the
R22 Group
Group
(compare2.2.3.
entries
and
3).the
Effect
of
R
2.2.3.
of
R
(compare
entries
22Effect
and
3).
2.2.3.
Effect
of the
the
R22 Group
Group
2.2.3. Effect of the R2 Group
To extend
extend
the scope
scope
of the
the reaction,
reaction,
it was
was
also
important
to compare
compare
the reactivity
reactivity
of pyridinium
pyridinium
To
extend
the the
scope
of
the
reaction,
it
was
also
important
to
compare
the
reactivity
of
pyridinium
To
of
it
important
to
the
of
To
extend
scope
of
the
reaction,
it
also
important
to
compare
the
reactivity
of
ToTable
extend
the
scope
of
the
reaction,
it2was
was
alsoalso
important
toof
compare
the
reactivity
of pyridinium
pyridinium
5.the
Effect
of
the
nature
of
R
group
on
the
yield
7-cyanoquinazolines.
salts
containing
various
methylene
R
2 substituents.
As
shown
in
Table
5,
the
yield
in
7-cyanoindolizine
salts
containing
various
methylene
R
2
substituents.
As
shown
in
Table
5,
the
yield
in
7-cyanoindolizine
Table
5.
Effect
of
the
nature
of
R
2
group
on
the
yield
of
7-cyanoquinazolines.
containing
various
methylene
R2 substituents.
As shown
in Table
5, the
yield
in 7-cyanoindolizine
salts
containing
various
methylene
R
As
shown
in
5,
yield
in
7-cyanoindolizine
saltssalts
containing
various
methylene
R22 substituents.
substituents.
Asfrom
shown
in Table
Table
5, the
the
yield
in9.
7-cyanoindolizine
was
higher
starting
from
the methyl
methyl
ester
7 than
than
benzoyl
derivatives
89.or
or
The
presence
of the
the
was
higher
starting
from
the
methyl
ester
77 than
from
benzoyl
derivatives
88 or
The
presence
of
the
was
higher
starting
from
the
ester
7
from
benzoyl
derivatives
8
9.
The
presence
of
was
higher
starting
from
the
methyl
ester
than
from
benzoyl
derivatives
or
9.
The
presence
of
wasnitro
higher
starting
fromphenyl
the methyl
ester
7 thanthe
from
benzoyl
derivatives
8 slightly
or 9. Theincreased
presence
of the
the
group
on
the
ring,
lowering
pH
of
ylide
formation,
the
yield
nitro
group
on
the
phenyl
ring,
lowering
the
pH
of
ylide
formation,
slightly
increased
the
yield
nitro
group
on
phenyl
ring,
lowering
of ylide
formation,
slightly
increased
yield
nitro
group
on
the
phenyl
ring,
lowering
the the
pH pH
of ylide
formation,
slightly
increased
the the
yield
nitro
group
on
the the
phenyl
(compare
entries
2 and
and
3).ring, lowering the pH of ylide formation, slightly increased the yield
(compare
entries
22 and
3).
(compare
entries
2
3).
(compare
entries
and
3).
(compare entries 2 and 3).
Table
5. Effect
of the nature
R2 group
on the yield
of 7-cyanoquinazolines.
Table
5. Effect
of the
of R
2of
group
on the
of 7-cyanoquinazolines.
Table
5. Effect
of nature
the nature
of
R2 group
on yield
the yield
of 7-cyanoquinazolines.
Table
Table 5.
5. Effect
Effect of
of the
the nature
nature of
of R
R22 group
group on
on the
the yield
yield of
of 7-cyanoquinazolines.
7-cyanoquinazolines.
Entry
1
2
3
4
Salt Salt
Indolizine
EntryPyridinium
Pyridinium
RR2 2
Indolizine
Yield (%) Yield (%)
7
OMe
20
1
81
7
OMe
20
81
8 8
Ph
50
Ph
24 24
2
50
9
C
H
NO
25
67
Entry
Pyridinium
Salt
R
2
Indolizine
Yield
(%)
6
4
2
Entry
Pyridinium
Salt
R
2 2R2
Indolizine
Yield
(%)
9Pyridinium
C6H4NO
25
3
67
Entry
Indolizine
Yield
(%)
Entry
Pyridinium
Salt
R
2
Indolizine
Yield
(%)
Entry
Pyridinium
SaltSalt
R
2
Indolizine
Yield
(%)
10
NHC
H
26
62
7
OMe
20
3
7
1
81
OMe
20
11 1 10 77 7
81
OMe
NHC
3H
7
26
4
OMe
20
81
7
OMe
20 20
1
816281
8 propiolate
Ph stirred
2
50 presence of K CO
8 ethyl
Ph were
24in24
2 equivalents
The pyridinium salts and 1.5
of
methanol50
in the
2
3
8 ethyl propiolate
Ph were24
24 in methanol
88 of
Ph
22 2equivalents
50
The
pyridinium salts and 1.5
in the presence
Ph
24stirred
50 50
(1 eq.) for 18 h at room temperature.
C
6H4NO
2
25
67
99 99
C
6HC
4NO
2
25
33 33
67
6H4NO
2
25
67
C
6H4NO
2
25
67
9
C6HNHC
4NO2
25
67 62
of K2CO3 (1 eq.) for 18 h at3room
4 temperature.
10 10
NHC
3H7 3H7
26 26
44 4
4
10
10 10
NHC
NHC
3H7 3H7
NHC
3H7
26
26 26
62
62
62 62
The
pyridinium
salts
and
1.5 equivalents
of ethyl
propiolate
were
stirred
in methanol
in the
presence
The
pyridinium
salts
and
1.5
equivalents
ethyl
propiolate
were
stirred
in
methanol
insalt
the
An interesting
result
was
obtained
withof
the
containing
pyridinium
10.presence
The yield of
The
pyridinium
salts
and
1.5 equivalents
ofamide
ethyl
propiolate
were
stirred
in methanol
in presence
the
The
pyridinium
salts
and
1.5
equivalents
of
ethyl
propiolate
were
in
the
Theof
pyridinium
saltsfor
and
1.5
of
ethyl
propiolate
were stirred
stirred
in methanol
methanol in
insalt
the presence
presence
An interesting
was
obtained
with
the
amide
containing
pyridinium
10. The yield of
3 (1 eq.)
18
h
atequivalents
room
temperature.
Kresult
2CO
32CO
(1
eq.)
for
18
h
at
room
temperature.
of
K
3 (1 eq.)
forh18
hroom
at room
temperature.
of
K23CO
2CO
(1
eq.)
for
18
at
temperature.
of
K
indolizine 26 was
moderate
(62%),
but
this
result
was
important
as
it
gives
an
interesting
alternative
to
of K2CO3 (1 eq.) for 18 h at room temperature.
indolizine 26 was moderate (62%), but this result was important as it gives an interesting alternative
the ester as a potential
reactant,
andwas
thisobtained
approach
has
not
been
reported
so farsalt
insalt
theThe
literature.
An
interesting
result
with
the
amide
containing
pyridinium
10.
The
yield
of
interesting
result
was
obtained
with
the
amide
containing
pyridinium
10.
yield
of
An
interesting
result
was
obtained
with
amide
containing
pyridinium
10.
yield
to the ester as An
a potential
reactant,
and
this
approach
has
not
been reported
so salt
farsalt
in
literature.
An
interesting
result
was
obtained
with
the
amide
containing
pyridinium
10.
The
yield
of
An
interesting
result
was
obtained
with
the the
amide
containing
pyridinium
salt
10. the
TheThe
yield
of of
indolizine
26 was
was
moderate
(62%),
but
this
result
was
important
as it
it gives
gives
an interesting
interesting
alternative
indolizine
26
moderate
(62%),
but
this
result
was
important
as
an
alternative
indolizine
26
moderate
(62%),
result
important
an
alternative
indolizine
26 was
was
moderate
(62%),
butbut
thisthis
result
waswas
important
as it
itasgives
gives
an interesting
interesting
alternative
indolizine
26 was
moderate
(62%),
butand
thisthis
result
was important
as it gives
an interesting
alternative
2.2.4. Influence
of ester
the
to the
the
as
potential
reactant,
approach
has
not
been
reported
so in
farthe
in the
the
literature.
to
the
ester
as
aaDipolarophile
potential
reactant,
and
this
approach
has
not
been
reported
so
far
literature.
to
aa potential
reactant,
approach
been
reported
so
far
in
literature.
to
ester
as
reactant,
and
this
approach
has
not
been
reported
so
in
literature.
2.2.4. Influence
of ester
the
to the
the
ester
as Dipolarophile
aaspotential
potential
reactant,
andand
thisthis
approach
hashas
notnot
been
reported
so far
far
in the
the
literature.
The last2.2.4.
parameter
toofevaluate
was the nature of the dipolarophile. As shown in Table 6, the
Influence
the Dipolarophile
Dipolarophile
2.2.4.
Influence
of
the
Dipolarophile
2.2.4.
Influence
ofevaluate
the
The last
parameter
to
was the nature of the dipolarophile. As shown in Table 6, the
2.2.4.
Influence
of
the
Dipolarophile
2.2.4.
Influence
of
the
Dipolarophile
reaction worked also well with propiolic amide such as 27, giving the corresponding indolizine 28
The
last
parameter
to evaluate
evaluate
was
the
nature
ofgiving
the
dipolarophile.
As shown
shown
in Table
Table
6, the
the in
The
last
parameter
evaluate
was
the
nature
the
dipolarophile.
As
shown
in
Table
6,
the
reaction worked
also
well
withto
propiolic
amide
such
asof
27,
the corresponding
indolizine
28
The
last
parameter
to
was
the
nature
of
the
dipolarophile.
As
in
6,
The
last
parameter
to
evaluate
was
the
nature
of
the
dipolarophile.
As
shown
in
6,
in reasonablereaction
(not
optimized)
yield.
With
substituted
propiolate,
such
as
a complex
mixture
of
The
last
parameter
to
evaluate
was
theamide
nature
of
the
dipolarophile.
As29,
shown
in Table
Table
6, the
the
worked
also
well
with
propiolic
such
as
27,
giving
the
corresponding
indolizine
28
in of
reaction
worked
also
well
with
propiolic
amide
such
as
27,
giving
the
corresponding
indolizine
28
in
reasonablereaction
(not
optimized)
yield.
With
substituted
propiolate,
such
ascorresponding
29, a complex
mixture
reaction
worked
also
well
with
propiolic
amide
such
as giving
27,
giving
the
indolizine
28 in
worked
also
well
with
propiolic
amide
such
as
27,
the
corresponding
indolizine
28
in
reaction
worked
also
well
with
propiolic
amide
such
as
27,
giving
the
corresponding
indolizine
28
in
indolizines
was
obtained
as
shown
by
the
presence
of
several
fluorescent
spots
on
TLC.
No
reaction
reasonable
(not
optimized)
yield.
With
substituted
propiolate,
such
as 29,
29,
complex
mixture
of
reasonable
(not
optimized)
With
substituted
propiolate,
such
as
29,
aa complex
mixture
of
reasonable
With
substituted
propiolate,
such
as
aaon
complex
mixture
reasonable
(not
optimized)
yield.
With
substituted
propiolate,
such
as
mixture
of
indolizines
was
obtained
asoptimized)
shownyield.
byyield.
the
presence
of several
fluorescent
spots
TLC.
No
reaction
reasonable
(not(not
optimized)
yield.
With
substituted
propiolate,
such
as 29,
29,
a complex
complex
mixture
of of
was observed
with
less
activated
alkynes,
as
exemplified
by
30
or
31.
indolizines
was
obtained
as
shown
by
the
presence
of
several
fluorescent
spots
on
TLC.
No
reaction
indolizines
was
obtained
as
shown
by
the
presence
of
several
fluorescent
spots
on
TLC.
No
reaction
indolizines
obtained
as shown
byexemplified
the
presence
of
spots
on TLC.
reaction
indolizines
was
obtained
asalkynes,
shown
by
the
presence
of
spots
on TLC.
No No
reaction
was observed
with
less
activated
as
byseveral
30byfluorescent
or30fluorescent
31.
indolizines
waswas
obtained
shown
by
the
presence
of several
several
fluorescent
was
observed
with lessasactivated
alkynes,
as exemplified
or 31. spots on TLC. No reaction
was
observed
with
less
activated
alkynes,
as
exemplified
by
30
observed
with
activated
alkynes,
as exemplified
byor
3031.
or 31.
was
observed
with
less
activated
alkynes,
as
by
or
31.
waswas
observed
lessless
activated
alkynes,
as exemplified
exemplified
by 30
30
or
31.
Table with
6. Reaction
of 4-cyanopyridinium
salt 7 with
various
dipolarophiles.
Table
6. Reaction
of 4-cyanopyridinium
7 with
various
dipolarophiles.
Table 6.Table
Reaction
4-cyanopyridinium
salt
with
various
dipolarophiles.
6. Reaction
of 4-cyanopyridinium
salt7 salt
7salt
with
various
dipolarophiles.
Table
6.of
Reaction
of 4-cyanopyridinium
7 with
various
dipolarophiles.
Table
Table 6.
6. Reaction
Reaction of
of 4-cyanopyridinium
4-cyanopyridinium salt
salt 77 with
with various
various dipolarophiles.
dipolarophiles.
Entry
Dipolarophile
Indolizine (Yield)
Entry
Dipolarophile
Indolizine
(Yield)
Dipolarophile
Indolizine
(Yield)
Entry Entry
(Yield)
Entry Dipolarophile
Dipolarophile Indolizine
Indolizine
(Yield)
Entry
Dipolarophile
Indolizine
(Yield)
Entry
Dipolarophile
Indolizine
(Yield)
CN
CN CN
CN
CN
CN
1
1
11 11
1
EtO
EtO
EtOEtO
EtO EtO
O
O
O
O
O
O
N
N N
N
N
N
MeO
MeOMeO
MeO
MeO
O
MeO O
O
O
O
O
O O
O
OO
OEt
OEt OEt
OEt
OEt
OEt
20
(81%)
20 (81%)
(81%)
20
O(81%)
20
20
20 (81%)
(81%)
2
22 22
2
2
3
33 33
3
O
O O
O
O
N
N N
N
H
OH
N H
H
H
27
N 27 27
27
H 27
27
27
COOEt
COOEt
COOEt
COOEt
COOEt
29
29
29
29 29
29
COOEt
3
29
20 (81%)
28 (40%)
(40%)
28
(40%)
28
28
28 (40%)
28 (40%)
(40%)
Complex
mixture
Complex
mixture
Complex
mixture
Complex
mixture
28 (40%)
Complex
mixture
Complex
mixture
Complex mixture
Molecules 2016, 21, 332
7 of 15
Molecules 2016, 21, 332
7 of 15
Table 6. Cont.
O
Molecules 2016, 21, 332
Molecules 2016, 21, 332 Entry
EtO
4
N
NH
H
5
5
5
(0%)(0%)
(0%)
30
O
30
30
30
O
N
O
O
H
5
7 of 15
7 of 15
Indolizine (Yield)
(0%)
O
O
EtO
EtO
4
4
4
Dipolarophile
31
O
O
(0%)
(0%)
(0%)(0%)
31
Stoichiometric amounts of 4-cyanopyridinium 31
7, the chosen dipolarophile and K2CO3 in methanol
Stoichiometric
of 4-cyanopyridinium
7, thedipolarophile
chosen dipolarophile
and
2CO3 in methanol
Stoichiometric
amounts amounts
of 4-cyanopyridinium
7, the chosen
and K2 CO
were stirred
3 inKmethanol
Stoichiometric
amounts
of
4-cyanopyridinium
7, are
the chosen
dipolarophile
and
K2COthe
3 in methanol
were
stirred
roomfor
forgiven
18
Yields
after
purification
indolizines
at room
temperature
18 h. temperature
Yields are
after
purification
of the
indolizines
by column
chromatography
wereatstirred
attemperature
room
forh.18
h. Yields
aregiven
given
after
purification
of of
the indolizines
by by
were
stirred at room temperature for 18 h. Yields are given after purification of the indolizines by
(elutionchromatography
EtOAc/cyclohexane).
column
(elution
EtOAc/cyclohexane).
column chromatography
(elution
EtOAc/cyclohexane).
column chromatography (elution EtOAc/cyclohexane).
Again,
it is important
to emphasize
the
mild conditions used
used in this
study.
Simple
pyridinium
Again, itAgain,
is important
to emphasize
thethe
mild
this
study.
Simple
pyridinium
it is important
to emphasize
mildconditions
conditions used ininthis
study.
Simple
pyridinium
ylides were shown to react at high temperatures with isolated alkynes [39]. However the lack of
ylides were
shown
to react
at
high
temperatures
with
isolated
alkynes
[39].
However
ylides
were shown
to react
at
high
temperatures
with
isolated
alkynes
[39].
However
the
lack
at high temperatures with isolated alkynes [39]. However theoflack of
reactivity with isolated alkynes at room temperature may be useful as it allows the introduction of
reactivity
with
isolated
alkynes
at room
temperature
may
beuseful
useful
asas
it allows
allows
the
introduction
of of an
reactivityan
with
isolated alkynes
alkynes
room
temperature
may
useful
it allows
introduction
of
with
isolated
atatroom
temperature
may
bebe
as
it
thethe
introduction
isolated triple bond in the reactants for further orthogonal reactions.
an
isolated
triple
bond
in
the
reactants
for
further
orthogonal
reactions.
an
isolated
triple
bond
in the
reactants
further
orthogonal
reactions.
isolated
triple
bond
in the
reactants
for for
further
orthogonal
reactions.
3. Discussion
3. Discussion
3. Discussion
Discussion
3.
To summarize, the highest yields of indolizines were obtained when both partners of the reaction,
To summarize, the highest yields of indolizines were obtained when both partners of the reaction,
the pyridinium
salt
(or theyields
corresponding
ylide) and
theobtained
triple bond,
wereboth
substituted
with
strong
To summarize,
the
highest
of indolizines
indolizines
were
when
partners
ofaathe
the
reaction,
To
summarize,
thesalt
highest
of
were
when
partners
reaction,
the pyridinium
(or theyields
corresponding
ylide) and
theobtained
triple bond,
wereboth
substituted
withof
strong
electron-withdrawing
group
(acetyl,
cyano,
ester,
or
amide).
The
mechanism
of
the
cycloaddition
has
the
pyridinium
salt
(or
the
corresponding
ylide)
and
the
triple
bond,
were
substituted
with
a
electron-withdrawing
group (acetyl, cyano,
ester,
or amide).
Thebond,
mechanism
the cycloaddition
the pyridinium
salt (or the corresponding
ylide)
and
the triple
wereofsubstituted
withhas
a strong
strong
been discussed in the literature. The reactions of pyridinium ylides with propiolates are generally
been
discussed
in
the
literature.
The
reactions
of
pyridinium
ylides
with
propiolates
are
generally
electron-withdrawing group
group (acetyl,
(acetyl, cyano,
cyano, ester,
ester, or
or amide).
amide). The
The mechanism
mechanism of
of the
the cycloaddition
cycloaddition has
has
electron-withdrawing
described as concerted OM-controlled reactions [33,40,43,44]. Matsumoto [41] also reported the inverse
describedinasthe
concerted
OM-controlled
reactionsof[33,40,43,44].
Matsumoto
[41] also
reported theare
inverse
been
discussed
literature.
The
reactions
pyridinium
ylides
with
propiolates
generally
been discussed
in the literature.
The of
reactions
of pyridinium
ylides
with propiolates are generally
electron-demand
cycloaddition
cyclooctyne
with pyridinium
bis(methoxycarbonyl)methylides
electron-demand cycloaddition of cyclooctyne with pyridinium bis(methoxycarbonyl)methylides
describedsimilar
as concerted
concerted
OM-controlled
reactions
[33,40,43,44].
Matsumoto
[41] also
also
the inverse
inverse
to 11. However,
Shang and
colleagues
[39] found that,
in the reaction
withreported
simple alkynes
described
as
OM-controlled
reactions
[33,40,43,44].
Matsumoto
[41]
the
similar to 11. However, Shang and colleagues [39] found that, in the reaction
withreported
simple alkynes
in DMF–Kcycloaddition
2CO3 at high temperature
(120 °C),with
the presence
of electron-donating
or –withdrawing
electron-demand
of cyclooctyne
pyridinium
bis(methoxycarbonyl)methylides
electron-demand
of
cyclooctyne
pyridinium
bis(methoxycarbonyl)methylides
in DMF–K2cycloaddition
CO3 at high temperature
(120 °C),with
the presence
of electron-donating
or –withdrawing
substituents
on theShang
ylides significantly
lowered
thefound
yields in
indolizines.
similar tosubstituents
11.
However,
and
colleagues
[39]
that,
in
the
reaction
with
simple alkynes
11. However,
colleagues
on theShang
ylides significantly
lowered the yields in indolizines.
The importance of electron-withdrawing
groups on both reactants is in favor of the two-step
˝
The
importance
of electron-withdrawing
groups
on both
is in favor of or
the–withdrawing
two-step
CO
at high
high temperature
temperature
(120 °C),
C), the
the
electron-donating
in DMF–K
22CO
33 at
(120
presence
ofreactants
mechanism depicted in Scheme 2, involving the Michael addition of the ylide to the triple bond, with
mechanism
depicted
in Scheme 2, involving
the
Michael
addition
of the ylide to the triple bond, with
ylides
significantly
lowered
the
yields
in
indolizines.
substituents
on
the
yields
in
indolizines.
formation of zwitterionic allenoate intermediate followed by the intramolecular 5-endo trig cyclization.
of zwitterionic
allenoate intermediate
followed
the intramolecular
trig cyclization.
The formation
importance
electron-withdrawing
groups
onbyboth
both
reactants
is5-endo
in favor
of the
importance
electron-withdrawing
is
However, one of
also
has to keep in mind that groups
the very on
first
step isreactants
not the cycloaddition
itself,
buttwo-step
the
However, one also has to keep in mind that the very first step is not the cycloaddition itself, but the
formation
andin
stabilization
ofinvolving
the reactive the
ylides
that are addition
also favored
by
electron-withdrawing
groups.
mechanism
depicted
Scheme
2,
Michael
of
the
ylide
to
the
triple
bond,
formation and stabilization of the reactive ylides that are also favored by electron-withdrawing groups. with
formation of zwitterionic allenoate intermediate
intermediate followed
followed by
by the
the intramolecular
intramolecular 5-endo
5-endo trig
trigcyclization.
cyclization.
R
R1
R1
R11 to keep in mind
However, one also has
that
the
very
first
step
is
not
the
cycloaddition
itself,
but the
R1
R1
not the cycloaddition
Michael
O Michael
1) Cyclization
addition
O
1)
Cyclization
of the
the reactive
reactive
ylides that
thatare
arealso
alsofavored
favored
byelectron-withdrawing
electron-withdrawinggroups.
groups.
formation and stabilization of
by
additionylides
O
O
N
R2
OEt
OEt
N
N
R
R1R22
O
OEt
N
N
OEt
R2
OEt
R2 R1
O
O
O
O
allenoate intermediate
allenoate intermediate
Michael
addition
N
2) spontaneous
2)
spontaneous
oxidation
R
oxidation
R2
2
1) Cyclization
O
O
2) spontaneous
Scheme 2. Alternative two-step mechanism.
oxidation
OEt mechanism.
SchemeR2. Alternative two-step
2
N
N
R1
N
R2
CO Et
CO22Et
CO2Et
In conclusion, the reaction of pyridinium
ylides with
propiolic acid derivativesOwas explored in the
O In
O ylides
O propiolic
conclusion, the reaction of pyridinium
with
acid derivatives was explored in the
perspective of its use as coupling reaction. The reaction was investigated by varying a set of parameters,
perspective of its use as coupling reaction.
The reaction
was investigated by varying a set of parameters,
allenoate
intermediate
i.e., the nature of the substituents, the reaction conditions, and the nature of the dipolarophile. First of
i.e., the nature of the substituents, the reaction conditions, and the nature of the dipolarophile. First of
all, the regioselectivity of the reaction is a positive aspect for this application. The presence of an
all, the regioselectivity ofScheme
the reaction
is a positive
aspect mechanism.
for this application. The presence of an
2.
two-step
Scheme
2. Alternative
Alternative
two-step
mechanism.
electron-withdrawing group
at position
4 of the pyridinium
salt (exemplified with 4-cyano or 4-acetyl
electron-withdrawing group at position 4 of the pyridinium salt (exemplified with 4-cyano or 4-acetyl
derivatives) allowed the reaction with propiolic ester or amide to proceed in mild conditions in a variety
derivatives)the
allowed the reaction
with propiolic
ester or amide
to proceed
in
mild conditions
a variety in the
In conclusion,
pyridinium
propiolic
aciddue
derivatives
wasinexplored
of solvents. Thereaction
reactionof
progression
wasylides
easily with
monitored
by TLC,
to the fluorescence
of the
In conclusion,
of
pyridinium
with
propiolic
acid
derivatives
was explored
of solvents. the
Thereaction
reaction progression
was ylides
easily monitored
by TLC,
due
to the fluorescence
of the in the
perspective
of its use asindolizine.
coupling This
reaction.
was investigated
varying
a set of parameters,
newly-formed
pointThe
is ofreaction
major interest
is that, so far,by
most
pro-fluorescent
click
perspective
of
its
use
as
coupling
reaction.
The
reaction
was
investigated
by
varying
a
set
of
parameters,
newly-formed indolizine. This point is of major interest is that, so far, most pro-fluorescent click
reactions
involve
the use of added
fluorogenic
or fluorescent
heterocycles
[50,51].
i.e., the nature
of
the
substituents,
the
reaction
conditions,
and
the
nature
of
the
dipolarophile.
First of
reactions
the use of added
fluorogenic
or fluorescent
heterocycles
[50,51].
i.e., the nature
of involve
the substituents,
the reaction
conditions,
and
the nature
of the dipolarophile. First
all, the regioselectivity of the reaction is a positive aspect for this application. The presence of an
of all, the regioselectivity of the reaction is a positive aspect for this application. The presence of an
electron-withdrawing group at position 4 of the pyridinium salt (exemplified with 4-cyano or 4-acetyl
electron-withdrawing group at position 4 of the pyridinium salt (exemplified with 4-cyano or 4-acetyl
derivatives) allowed the reaction with propiolic ester or amide to proceed in mild conditions in a variety
derivatives) allowed the reaction with propiolic ester or amide to proceed in mild conditions in a
of solvents. The reaction progression was easily monitored by TLC, due to the fluorescence of the
newly-formed indolizine. This point is of major interest is that, so far, most pro-fluorescent click
reactions involve the use of added fluorogenic or fluorescent heterocycles [50,51].
Molecules 2016, 21, 332
8 of 15
variety of solvents. The reaction progression was easily monitored by TLC, due to the fluorescence of
the newly-formed indolizine. This point is of major interest is that, so far, most pro-fluorescent click
reactions involve the use of added fluorogenic or fluorescent heterocycles [50,51].
A second key result was the reactivity in neutral aqueous solutions at room temperature. Indeed,
the presence of the electron-withdrawing group at position 4 played an essential role in the formation
and stabilization of the reactive ylides in these conditions. The main limitation appeared to be the
water solubility of the propiolic ester.
This study allowed us to select the best partners and conditions for a highly modular
pro-fluorescent click-type coupling reaction. The reactants include a pyridine containing an
electron-withdrawing group (CN, COR, CO2 R, CONHR, etc.) at position 4, a 2-bromo-acetyl ester or
amide, and a propiolic ester or amide. Interestingly, this methodology appears complementary
to the tetrazine-alkene reaction [52,53] involving an electron-rich dipolarophile, but yielding
non-fluorescent compounds.
4. Experimental Section
4.1. Material and Methods
Melting points were determined using a Reichert Thermovar apparatus (Depew, NW, USA)
and are uncorrected. NMR spectra were recorded on the Bruker Avance 400 spectrometer (Bruker
Corporation, Billerica, MA, USA) of the “Fédération de Recherche” ICMG (FR2607) platform, using
the solvent as the internal reference; the chemical shifts are reported in parts per million (ppm)
units. High-resolution mass spectra (HRMS) were performed on a Bruker maXis mass spectrometer
Q-TOF (Bruker Corporation) by the “Fédération de Recherche” ICOA/CBM (FR2708) platform.
Reversed-phase HPLC was performed with a µ-bondapak-C18 analytical column (Waters Corporation,
Milford, MA, USA). A Waters chromatographic system was used, with two M-510 pumps and a
photodiode array detector Waters 996 using Millenium 32 software. A linear gradient from 0 to 100%
methanol in H2 O pH 2.5 (phosphoric acid), 2 mL/min flow rate, was used.
The reagents were purchased from Sigma Aldrich and were used without further purification.
N-Benzylprop-2-ynamide 27 was prepared by biocatalyzed reaction between benzylamine and ethyl
propiolate as reported recently by us [54]. Ethyl 3-ethynylbenzoate 30 was prepared by esterification
of 3-ethynylbenzoic acid following reported procedure [55].
Calculator Plugins were used for structure property prediction and calculation, Marvin 6.0.2 ,
2013, ChemAxon (http://www.chemaxon.com).
Copies of the NMR spectra and HPLC chromatograms of the new compounds may be found in
the Supplementary Materials.
4.2. General Methods for the Synthesis of N-Heterocyclic Salts
Method A: The pyridine derivative (1 eq.) and the alkylating reagent (1.5 eq) were dissolved
in dry acetone (2 mL for 1 mmol of pyridine derivative). The reaction mixture was stirred in an
ultra-sound bath for 5 h to 10 h, depending on the nature of substituent present on the pyridine. The
temperature of the bath was kept under 50 ˝ C by adding ice is necessary. Then, a non-polar solvent
(3 to 5 mL of Et2 O or DCM) was added, and the quaternary salt that deposited was filtered off, and
washed with DCM.
Method B: The reactions between the pyridine derivatives and diethyl iodomalonate were
performed in acetone in the presence of a large excess of reactant, the mixture being stirred at room
temperature for two days. Then, Et2 O was added to the flask and the quaternary hygroscopic salt was
filtered off and washed with DCM and/or Et2 O.
1-(2-Methoxy-2-oxoethyl)pyridinium bromide (1) was prepared according to the general method A from
pyridine (1 mmol) and methyl 2-bromoacetate. The resulting pyridinium 1 was obtained in 71% yield
Molecules 2016, 21, 332
9 of 15
(165 mg) as a white powder. mp 167–168 ˝ C [lit. [56] 174–175 ˝ C]; 1 H-NMR (400 MHz, CD3 OD) δ 9.01
(dd, 2H, J = 6.8, 1.2 Hz), 8.74 (m, 1H), 8.23 (t, 2H, J = 7.6, 6.8 Hz), 5.66 (s, 2H), 3.90 (s, 3H).
4-Amino-1-(2-methoxy-2-oxoethyl)pyridinium bromide (2) was prepared according to the general method
A from 4-aminopyridine (1 mmol) and methyl 2-bromoacetate. The resulting pyridinium salt 2 was
obtained in 83% yield (205 mg) as a white powder. mp 268–269 ˝ C [lit. [57] 175–176 ˝ C]; 1 H-NMR
(400 MHz, CD3 OD) δ 8.09 (dd, J = 6 Hz, 2H), 6.92 (dd, J = 6 Hz, 2H), 5.12 (s, 2H), 3.86 (s, 3H).
4-Acetamido-1-(2-methoxy-2-oxoethyl)pyridinium bromide (3) was prepared according to the general
method A from 4-acetamidopyridine (1 mmol) and methyl 2-bromoacetate The resulting pyridinium
salt 3 was obtained in 81% yield (234 mg) as a white powder. mp 104–106 ˝ C; 1 H-NMR (400 MHz,
DMSO-d6 ) δ 11.61 (s, 1H), 8.74 (d, 2H, J = 7.6 Hz), 8.14 (d, 2H, J = 7.2 Hz), 5.51 (s, 2H), 3.78 (s, 3H), 2.26
(s, 3H); 13 C-NMR (100 MHz, DMSO-d6 ) δ 171.1, 167.3, 152.5, 146.6, 114.3, 58.6, 53.0, 24.7; HRMS (ESI)
m/z calcd for C10 H13 N2 O3 209.0926, obsd 209.0919.
4-Trifluoromethyl-1-(2-methoxy-2-oxoethyl)pyridinium bromide (4) was prepared according to the general
method A from commercial 4-trifluoromethylpyridine (2 mmol) and methyl 2-bromoacetate. The
resulting quaternary salt 4 was obtained in 54% yield (162 mg) as a yellow powder. mp 127–130 ˝ C;
1 H-NMR (400 MHz, CD OD) δ 9.39 (d, 2H, J = 6.8 Hz), 8.66 (d, 2H, J = 6.8 Hz), 5.83 (s, 2H), 3.94 (s, 3H);
3
13 C-NMR (100 MHz, CD OD) δ 165.9, 148.6 (2C), 145.9, 145.5, 124.6 (2C), 122.5, 119.8, 61.0, 52.8; HRMS
3
(ESI) m/z calcd for C9 H9 F3 NO2 220.0577, obsd 220.0580.
4-(N-Propylcarbamoyl)-1-(2-methoxy-2-oxoethyl)pyridinium bromide (5) was pepared according to the
general method A from 4-N-propylcarbamoylpyridine (0.9 mmol) and methyl 2-bromoacetate.
The resulting quaternary salt 5 was obtained in 80% yield (231 mg) as an orange powder. mp
136–138 ˝ C; 1 H-NMR (400 MHz, CD3 OD) δ 9.19 (dd, 2H, J = 6.4 Hz); 8.52 (dd, 2H, J = 6.4 Hz),
5.75 (s, 2H), 3.92 (s, 3H), 3.46 (t, 2H, J = 7.4 Hz), 1.71–1.76 (m, 2H), 1.05 (t, 3H, J = 7.4 Hz); 13 C-NMR
(100 MHz, CD3 OD) δ 167.6, 164.0, 151.8, 148.6 (2C), 1267.0 (2C), 61.8, 54.1, 43.3, 23.4, 11.7; HRMS (ESI)
m/z: [M + H]+ calcd for C12 H17 N2 O3 237.1234, obsd 237.1232.
4-Acetyl-1-(2-methoxy-2-oxoethyl)pyridinium bromide (6) was prepared according to the general method
A from 4-acetylpyridine (4.1 mmol) and methyl 2-bromoacetate. The resulting quaternary salt 6 was
obtained in 64% yield (716 mg) as a red powder. mp 149–150 ˝ C; 1 H-NMR (400 MHz, CD3 OD) δ 9.35
(dd, 2H, J = 6.8 Hz); 8.63 (dd, 2H, J = 6.8 Hz); 5.88 (s, 2H, CH2 ); 3.80 (s, 3H, OCH3 ), 2.78 (s, 3H, CH3 );
13 C-NMR (100 MHz, DMSO-d ) δ 195.5, 166.6, 149.2, 147.8 (2C), 125.7 (2C), 60.4, 53.3, 27.5; HRMS (ESI)
6
m/z calcd for C10 H12 NO3 194.0812, obsd 194.0810.
4-Cyano-1-(2-methoxy-2-oxoethyl)pyridinium bromide (7) was prepared according to the general method
A from 4-cyanopyridine (1 mmol) and methyl 2-bromoacetate. The resulting pyridinium salt 7 was
obtained in 60% yield (154 mg) as a white powder. mp 208–209 ˝ C [lit. [58] 181–183 ˝ C]; 1 H-NMR
(400 MHz, CD3 OD) δ 9.29 (dd, 2H, J = 5.4 Hz), 8.64 (dd, 2H, J = 5.4 Hz), 5.75 (s, 2H), 3.92 (s, 3H).
4-Cyano-1-(2-oxo-2-phenylethyl)pyridinium iodide (8) was prepared according to the general method B
from commercial 4-cyanopyridine (2 mmol) and 2-iodo-acetophenone. The resulting pyridinium salt 8
was obtained in 70% yield (493 mg) as a red powder. mp 132–134 ˝ C [lit. [47] 114–118 ˝ C]; 1 H-NMR
(400 MHz, DMSO-d6 ) δ 9.30 (d, 2H, J = 6.9 Hz), 8.84 (d, 2H, J = 6.9 Hz), 8.09 (dd, 2H, J = 8.5, 7.1 Hz),
7.80–7.85 (m, 1H), 7.67–7.72 (m, 2H), 6.61 (s, 2H).
4-Cyano-1-(2-oxo-2-(para-nitrophenyl)ethyl)pyridinium iodide (9) was prepared according to the general
method A from commercial 4-cyanopyridine (1 mmol) and 2-iodo-4-nitroacetophenone. The resulting
quaternary salt 9 was obtained in 60% yield (239 mg) as a yellow powder. mp 182–184 ˝ C [lit. [47]
187–189 ˝ C]; 13 C-NMR (100 MHz, DMSO-d6 ) δ 189.2, 150.7, 147.6 (2C), 138.0, 130.8 (2C), 129.8 (2C),
128.1, 124.2 (2C), 114.8, 67.3.
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4-Cyano-1-[(N-propylcarbamoyl)methyl]pyridinium bromide (10) was prepared according to the general
method A from 4-cyanopyridine (1 mmol) and 2-bromo-N-propylacetamide. The resulting
pyridinium-salt 10 was obtained in 60% yield (160 mg) as a yellow powder. mp 185–186 ˝ C; 1 H-NMR
(400 MHz, CD3 OD) δ 9.24 (d, 2H, J = 6.8 Hz), 8.59 (d, 2H, J = 6.8 Hz), 5.60 (s, 2H), 3.26 (t, 2H, J = 7.2 Hz),
1.58–1.64 (m, 2H), 0.99 (t, 3H, J = 7.2 Hz); 13 C-NMR (100 MHz, CD3 OD) δ 165.0, 149.1 (2C), 131.7 (2C),
130.4, 115.3, 63.9, 42.9, 23.5, 11.8; HRMS (ESI) m/z: [M + H]+ calcd for C11 H14 N3 O 204.1131, obsd
204.1132.
1-(1,3-Diethoxy-1,3-dioxopropan-2-yl)pyridinium iodide (11) was prepared according to the general method
B from pyridine (5.5 mmol) and ethyl 2-iodomalonate. The resulting quaternary salt 11 was obtained
in 89% yield (1.80 g) as a white powder. mp 151–152 ˝ C [lit. [59] 154–155 ˝ C]; 1 H-NMR (400 MHz,
CD3 OD) δ 9.20 (t, 2H, J = 7.2 Hz), 8.81–8.85 (m, 1H), 8.28 (dd, 2H, J = 7.2 Hz, 8 Hz), 4.37–4.52 (m, 4H),
1.40 (t, 6H, J = 7.2 Hz).
4-Acetyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)pyridinium iodide (12) was prepared according to the general
method B from 4-acetylpyridine (4 mmol) and ethyl 2-iodomalonate. The resulting pyridinium-salt 12
was obtained in 99% yield (1.66 g) as a yellow powder. mp 130–131 ˝ C [lit. [37]: 196–198 ˝ C]; 1 H-NMR
(400 MHz, CD3 OD) δ 9.36 (d, 2H, J = 7.0 Hz), 8.61 (d, 2H, J = 7.0 Hz), 4.39–4.51 (m, 4H), 2.84 (s, 3H),
1.41 (t, 6H, J = 7.1 Hz).
4-Cyano-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)pyridinium iodide (13) [37] was prepared according to
the general method B from 4-cyanopyridine (4.8 mmol) and ethyl 2-iodomalonate. The resulting
pyridinium-salt 13 was obtained in 40% yield (750 mg) as a white powder. mp 120–122 ˝ C [lit. [37]
240 ˝ C decomposed]; 13 C-NMR (100 MHz, CD3 OD) δ 163.3 (2C), 151.6, 149.7 (2C), 132.0, 131.4 (2C),
115.2, 65.8 (2C), 14.2 (2C).
4.3. General Methods for the Ylide-Alkyne Cycloaddition
Method C: The cycloaddition was performed with 1 eq. of the quaternary salt, 1.1 eq. of the
alkyne derivative, and 1 eq. of K2 CO3 in methanol or DMF. The pH of the solution was close to 9.
The reaction mixture was stirred at room temperature under air atmosphere for 18 h. Then, water was
added and the corresponding indolizine was precipitated, filtered off and washed with water.
Method D: The cycloaddition was performed in Tris-buffer pH 7.5 (Tris-buffered saline tablets
from sigma, one tablet dissolved in 15 mL of deionized water produces 50 mM Tris-HCl, 150 mM
sodium chloride) with 1 eq. of the quaternary salt and 1.1 eq of the alkyne derivative. The reaction
mixture was stirred at 40 ˝ C under air atmosphere for 18 h. Then, the reaction mixture cooled in an ice
bath, and the precipitate that formed was filtered off and washed with water.
1-Ethyl 3-methyl indolizine-1,3-dicarboxylate (14). The reaction was performed with 1 (100 mg) and ethyl
propiolate in methanol, following method C. The indolizine 14 was obtained in 59% yield (63 mg) as a
white powder. mp 97–99 ˝ C [lit. [60] 92–93 ˝ C]; 1 H-NMR (400 MHz, CDCl3 ) δ 9.56 (dd, 1H, J = 7.0,
1.2 Hz), 8.34 (m, 1H), 8.04 (s, 1H), 7.37 (m, 1H), 7.04 (td, 1H, J = 6.8, 1.2 Hz), 4.43 (q, 2H, J = 7.2 Hz), 3.97
(s, 3H), 1.47 (t, 3H, J = 7.2 Hz).
1-Ethyl 3-methyl 7-(propylcarbamoyl)indolizine-1,3-dicarboxylate (17). The reaction was performed with
5 (40 mg) and ethyl propiolate in methanol, following method C. The indolizine 17 was obtained in
66% yield (27 mg) as a white powder. mp 159–161˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.52 (m, 1H),
8.64 (dd, 1H, J = 1.2 Hz, 2.0 Hz), 8.00 (s, 1H), 7.47 (dd, 1H, J = 2.0 Hz, 5.2 Hz), 6.38 (s br, 1H), 4.39
(q, 2H, J = 7.2 Hz), 3.94 (s, 3H), 3.46 (m, 2H), 1.68 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 1.01(t, 3H,
J = 7.2 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 165.3, 164.1, 161.3, 137.7, 131.4, 127.9, 124.7, 117.1, 115.6,
113.1, 107.3, 60.3, 51.7, 42.0, 22.9, 14.5, 11.5; HRMS (ESI) m/z: [M + H]+ calcd for C17 H21 N2 O5 333.1443,
obsd 333.1445.
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1-Ethyl 3-methyl 7-acetylindolizine-1,3-dicarboxylate (18). The reaction was performed with 6 (100 mg)
and ethyl propiolate in methanol, following method C. The indolizine 18 was obtained in 77% yield
(40 mg) as a red powder. mp 151–152 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.55 (m, 1H), 8.98 (m, 1H), 8.07
(s, 1H), 7.57 (dd, 1H, J = 7.4 Hz, 1.9 Hz), 5.34 (s, 2H), 4.46 (q, 2H, J = 7.2 Hz), 4.00 (s, 3H), 2.75 (s, 3H),
1.49 (t, 3H, J = 7.2 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 196.0, 163.8, 161.3, 137.5, 132.8, 127.6, 124.8, 121.4,
116.4, 111.8, 109.0, 60.4, 51.8, 26.1, 14.5; HRMS (ESI) m/z: [M + H]+ calcd for C15 H16 NO5 290.1023, obsd.
290.1022, [M + Na]+ calcd for C15 H15 NNaO5 312.0842, obsd. 312.0840.
1-Ethyl 3-methyl 7-(trifluoromethyl)indolizine-1,3-dicarboxylate (19a) and 1-methyl 3-methyl 7-(trifluoromethyl)
indolizine-1,3-dicarboxylate (19b). The reaction was performed with 4 (50 mg) and ethyl propiolate in
methanol, following method C. The mixture of indolizines 19a and 19b (30/70 ratio) was obtained in
55% yield (27 mg) as a yellow powder. 1 H-NMR (400 MHz, CDCl3 ) δ 9.60 (d, 1H, J = 7.2 Hz), 8.64 (s,
1H), 8.04 (s, 1H), 7.12 (dd, 1H, J = 7.2, 2.0 Hz), 4.40 (q, 2H, J = 7.2 Hz, CH2 of 19a), 3.95 and 3.94 (2s,
2 ˆ 3H, OMe of 19a and 19b), 1.42 (t, 3H, J = 7.2 Hz, CH3 of 19a); 13 C-NMR (100 MHz, CDCl3 ) δ 164.0,
163.5, 161.3, 136.8, 128.4,127.16, 125.7 (q, 225 Hz, CF3 ), 124.9, 124.6, 121.9, 117.5, 117.4, 116.1, 110.1,
107.9, 60.5, 51.8, 51.6, 14.5; HRMS (ESI) 19a : m/z calcd for C14 H13 F3 NO4 316.0791, obsd 316.0796, 19b:
m/z calcd for C13 H11 F3 NO4 302.0635, obsd 302.0638.
1-Ethyl 3-methyl 7-cyanoindolizine-1,3-dicarboxylate (20). The reaction was performed with 7 (50 mg)
and ethyl propiolate in methanol, following method C. The indolizine 20 was obtained in 81% yield
(37 mg) as a white powder. mp 114–115 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.58 (dd, 1H, J = 7.2, 0.8 Hz),
8.74–8.75 (m, 1H), 8.06 (s, 1H), 7.07 (dd, 1H, J = 7.2, 2.0 Hz), 4.42 (q, 1H, J = 7.0 Hz), 3.98 (s, 3H), 1.44
(t, 3H, J = 7.2 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 163.2, 161.1, 136.0, 128.2, 125.9, 125.1, 117.5, 114.1,
109.0, 108.0, 60.7, 52.0, 14.5; HRMS (ESI) m/z: [M + H]+ calcd for C14 H13 N2 O4 273.0869, obsd 273.0870.
1,3-Diethyl 7-acetylindolizine-1,3-dicarboxylate (22) [61]. The reaction was performed with 12 (100 mg)
and ethyl propiolate, following method D. The indolizine 22 was obtained in 12% yield (9 mg) as a
white powder. mp 125–127 ˝ C. 1 H-NMR (400 MHz, DMSO-d6 ) δ 9.47 (dd, 1H, J = 0.8, 7.4 Hz), 8.81
(d, 1H, J = 0.8 Hz), 7.90 (s, 1H), 7.62 (dd, 1H, J = 1.9, 7.4 Hz), 4.35–4.40 (m, 4H), 2.69 (s, 3H), 1.35–1.41
(m, 6H).
1,3-Diethyl 7-cyanoindolizine-1,3-dicarboxylate (23). The reaction was performed with 13 (15 mg) and
ethyl propiolate, following method D. The indolizine 23 was obtained in 40% yield (4.9 mg) as a white
powder. mp 103–104 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.64 (dd, 1H, J = 0.8, 7.2 Hz), 8.78 (s, 1H), 8.11
(s, 1H), 7.11 (dd, 1H, J = 1.6, 7.2 Hz), 4.45–4.50 (m, 4H), 1.46–1.51 (m, 6H); 13 C-NMR (100 MHz, CDCl3 )
δ 163.2, 161.1, 136.1, 128.2, 125.8, 125.0, 117.5, 116.9, 114.1, 109.0, 108.0, 61.4, 60.7, 52.0, 14.5 (identical to
the commercial compound).
1-Ethyl 3-benzoyl-7-cyanoindolizine-1-carboxylate (24). The reaction was performed with 8 (50 mg) and
ethyl propiolate in methanol, following method C. The indolizine 24 was obtained in 50% yield
(22.4 mg) as an orange powder. mp 136–137 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.99 (d, 1H, J = 6.8 Hz),
8.83 (s, 1H), 7.95 (s, 1H), 7.87 (d, 2H, J = 6.8 Hz), 7.67 (d, 1H, J = 6.4 Hz), 7.60 (d, 2H, J = 7.2 Hz), 7.20
(d, 1H, J = 6.8 Hz), 4.47 (q, 2H, J = 7.2 Hz), 1.47 (t, 3H, J = 7.2 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 186.1,
163.2, 138.9, 136.9, 132.3, 129.3, 129.1, 129.0, 128.7, 128.4, 125.6, 124.2, 117.3, 114.8, 109.7, 109.4, 60.8,
14.53; HRMS (ESI) m/z calcd for C19 H15 N2 O3 319.1077, obsd 319.1081.
1-Ethyl 3-(4-nitrobenzoyl)-7-cyanoindolizine-1-carboxylate (25). The reaction was performed with 9 (50 mg)
and ethyl propiolate in methanol, following method C. The indolizine 25 was obtained in 67% yield
(29.6 mg) as a yellow powder. mp 143–144 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.92 (d, 1H, J = 7.2 Hz),
8.75 (s, 1H), 8.34 (d, 2H, J = 8.5 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.76 (s, 1H), 7.17 (m, 1H), 4.35 (q, 2H, J = 7.1
Hz), 1.35 (t, 3H, J = 7.1 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 183.9, 163.0, 150.0, 144.3, 137.7, 130.1, 129.9,
129.6, 129.3, 125.9, 124.1, 123.9, 123.6, 117.2, 115.7, 110.9, 110.2, 61.2, 14.7; HRMS (ESI) m/z: [M + H]+
calcd for C19 H14 N3 O5 364.0927, obsd 364.0928.
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1-Ethyl 7-cyano-3-(N-propylcarbamoyl)indolizine-1-carboxylate (26). The reaction was performed with
10 (20 mg) and ethyl propiolate in methanol, following method C. The indolizine 26 was obtained
in 62% yield (15.6 mg) as a white powder. mp 170–171 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ 9.83 (dd,
1H, J = 7.4, 1.0 Hz), 8.75 (dd, 1H, J = 1.8, 1.0 Hz), 7.80 (s, 1H), 7.08 (dd, 1H, J = 7.4, 1.8 Hz), 6.17 (br s,
1H), 4.51 (q, 2H, J = 7.2 Hz), 3.40–3.55 (m, 2H), 1.72–1.79 (m, 2H), 1.53 (t, 3H, J = 7.2 Hz), 1.10 (t, 3H,
J = 7.2 Hz); 13 C-NMR (100 MHz, CDCl3 ) δ 163.4, 160.7, 135.1, 128.7, 125.8, 119.9, 119.2, 117.7, 113.4,
108.2, 107.3, 60.7, 41.3, 23.0, 14.6, 11.5; HRMS (ESI) m/z: [M + H]+ calcd for C16 H18 N3 O3 300.1342, obsd
300.1348.
Methyl 1-(N-benzylcarbamoyl)-7-cyanoindolizine-3-carboxylate (28). The reaction was performed with
propiolamide 27 and pyridinium salt 7 (50 mg) in methanol, following method C. The indolizine 28
was obtained in 40% yield (26 mg) as a white powder. mp 196–199 ˝ C; 1 H-NMR (400 MHz, CDCl3 ) δ
9.56 (dd, 1H, J = 7.4, 1.2 Hz), 9.07 (dd, 1H, J = 1.8, 1.2 Hz), 7.77 (s, 1H), 7.42–7.44 (m, 4H), 7.36–7.39
(m, 1H), 7.10 (dd, 1H, J = 7.4, 1.8 Hz), 6.29 (br s, 1H), 4.72 (d, 2H, J = 5.6 Hz), 3.99 (s, 3H); 13 C-NMR
(100 MHz, CDCl3 ) δ 162.9, 160.9, 138.1, 136.0, 128.9 (2C), 128.0 (2C), 127.8, 127.7, 126.8, 120.1, 117.5,
116.3, 114.2, 111.5, 107.5, 51.9, 43.7; HRMS (ESI) m/z: [M + H]+ calcd for C19 H16 N3 O3 334.1186, obsd
334.1183, [M + Na]+ calcd for C19 H15 N3 O3 356.1006, obsd. 356.1007.
4.4. pKa Determination
Potentiometric measurements were performed in a jacketed cell thermostated at 25.0 ˝ C, kept
under an inert atmosphere of purified argon, using an automatic titrator (Metrohm, DMS Titrino
716, Herisau, Switzerland) connected to a microcomputer. The free hydrogen concentrations were
measured with a glass-Ag/AgCl combined electrode (Metrohm) filled with 0.1 M NaCl. The electrode
was calibrated with three standard buffers at pH 4, 7, and 10. NaCl was employed as supporting
electrolyte to maintain the ionic strength at 0.10 M.
Samples of 0.2 mmol of pyridinium salts were dissolved in 20 mL of fresly prepared 0.1 M NaClO4 .
Aliquot of 10 mL were titrated with 0.02 M NaOH. A minimum of three sets of data was used in each
case. Equilibrium constants and species distribution diagrams were calculated by using the program
HYPERQUAD 2003.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/ 1420-3049/
21/3/332/s1.
Acknowledgments: This work has been partly supported by the Labex ARCANE (ANR-11-LABX-0003-01)
and by a grant of the Romanian National Authority for Scientific Research, CNCS-UEFISCDI project number
PN-II-ID-PCE-2011-3-0226.
Author Contributions: M.D. and R.D. conceived the project; I.B. designed the experiments; S.B. and I.O.G.
performed the experiments; M.D. and I.B. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
DMF
DMSO-D6
TLC
TRIS
N,N-dimethylformamide
deuterated dimethylsulfoxide
thin-layer chromatography
Tris(hydroxymethyl)aminomethane
References
1.
Huang, W.; Zuo, T.; Luo, X.; Jin, H.; Liu, Z.; Yang, Z.; Yu, X.; Zhang, L.; Zhang, L. Indolizine derivatives as
HIV-1 VIF-elongin C interaction inhibitors. Chem. Biol. Drug Des. 2013, 81, 730–741. [CrossRef] [PubMed]
Molecules 2016, 21, 332
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
13 of 15
Singh, G.S.; Mmatli, E.E. Recent progress in synthesis and bioactivity studies of indolizines. Eur. J. Med. Chem.
2011, 46, 5237–5257. [CrossRef] [PubMed]
Vemula, V.R.; Vurukonda, S.; Bairi, C.K. Indolizine derivatives: Recent advances and potential
pharmacological activities. Int. J. Pharm. Sci. Rev. Res. 2011, 11, 159–163.
Chen, S.; Xia, Z.; Nagai, M.; Lu, R.; Kostik, E.; Przewloka, T.; Song, M.; Chimmanamada, D.; James, D.;
Zhang, S.; et al. Novel indolizine compounds as potent inhibitors of phosphodiesterase IV (PDE4):
Structure–activity relationship. MedChemComm 2011, 2, 176. [CrossRef]
Shen, Y.M.; Lv, P.C.; Chen, W.; Liu, P.G.; Zhang, M.Z.; Zhu, H.L. Synthesis and antiproliferative activity
of indolizine derivatives incorporating a cyclopropylcarbonyl group against Hep-G2 cancer cell line.
Eur. J. Med. Chem. 2010, 45, 3184–3190. [CrossRef] [PubMed]
Cheng, Y.; Ma, B.; Wudl, F. Synthesis and optical properties of a series of pyrrolopyridazine derivatives: Deep
blue organic luminophors for electroluminescent devices. J. Mater. Chem. 1999, 9, 2183–2188. [CrossRef]
Kim, E.; Koh, M.; Lim, B.J.; Park, S.B. Emission wavelength prediction of a full-color-tunable fluorescent core
skeleton, 9-aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one. J. Am. Chem. Soc. 2011, 133, 6642–6649. [CrossRef]
[PubMed]
Kim, E.; Koh, M.; Ryu, J.; Park, S.B. Combinatorial discovery of full-color-tunable emissive fluorescent
probes using a single core skeleton, 1,2-dihydropyrrolo[3,4-b]indolizin-3-one. J. Am. Chem. Soc. 2008, 130,
12206–12207. [CrossRef] [PubMed]
Kim, E.; Lee, S.; Park, S.B. 9-Aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one (Seoul-fluor) as a smart platform
for colorful ratiometric fluorescent pH sensors. Chem. Commun. 2011, 47, 7734–7736. [CrossRef] [PubMed]
Kim, E.; Lee, S.; Park, S.B. A Seoul-fluor-based bioprobe for lipid droplets and its application in image-based
high throughput screening. Chem. Commun. 2012, 48, 2331–2333. [CrossRef] [PubMed]
Lerner, D.A.; Evleth, E.M. Photophysical properties of indolizine and some azaindolizines. Chem. Phys. Lett.
1972, 15, 260–262. [CrossRef]
Liu, B.; Wang, Z.-J.; Wu, N.; Li, M.; You, J.; Lan, J. Discovery of a full-color-tunable fluorescent core
framework through direct C H (hetero)arylation of N-heterocycles. Chem. Eur. J. 2012, 18, 1599–1603.
[CrossRef] [PubMed]
Rotaru, A.V.; Druta, I.; Oeser, T.; Müller, T.J.J. A novel coupling 1,3-dipolar cycloaddition sequence as a
three-component approach to highly fluorescent indolizines. Helv. Chim. Acta 2005, 88, 1798–1812. [CrossRef]
Becuwe, M.; Landy, D.; Delattre, F.; Cazier, F.; Fourmentin, S. Fluorescent indolizine-β-cyclodextrin
derivatives for the detection of volatile organic compounds. Sensors 2008, 8, 3689–3705. [CrossRef]
Lungu, N.C.; Dépret, A.; Delattre, F.; Surpateanu, G.G.; Cazier, F.; Woisel, P.; Shirali, P.; Surpateanu, G.
Synthesis of a new fluorinated fluorescent β-cyclodextrin sensor. J. Fluor. Chem. 2005, 126, 385–388.
[CrossRef]
Hodgkiss, R.J.; Middleton, R.W.; Parrick, J.; Rami, H.K.; Wardman, P.; Wilson, G.D. Bioreductive fluorescent
markers for hypoxic cells: A study of 2-nitroimidazoles with 1-substituents containing fluorescent,
bridgehead-nitrogen, bicyclic systems. J. Med. Chem. 1992, 35, 1920–1926. [CrossRef] [PubMed]
Bayazit, M.K.; Coleman, K.S. Fluorescent single-walled carbon nanotubes following the 1,3-dipolar
cycloaddition of pyridinium ylides. J. Am. Chem. Soc. 2009, 131, 10670–10676. [CrossRef] [PubMed]
Wu, X.; Cao, H.; Li, B.; Yin, G. The synthesis and fluorescence quenching properties of well soluble hybrid
graphene material covalently functionalized with indolizine. Nanotechnology 2011, 22, 075202. [CrossRef]
[PubMed]
Kel'in, A.V.; Sromek, A.W.; Gevorgyan, V. A novel Cu-assisted cycloisomerization of alkynyl imines: Efficient
synthesis of pyrroles and pyrrole-containing heterocycles. J. Am. Chem. Soc. 2001, 123, 2074–2075. [CrossRef]
[PubMed]
Hardin, A.R.; Sarpong, R. Electronic effects in the Pt-catalyzed cycloisomerization of propargylic esters:
Synthesis of 2,3-disubstituted indolizines as a mechanistic probe. Org. Lett. 2007, 9, 4547–4550. [CrossRef]
[PubMed]
Chernyak, D.; Gevorgyan, V. Organocopper-mediated two-component S(N)21 -substitution cascade towards
N-fused heterocycles. Chem. Heterocycl. Compd. 2012, 47, 1516–1526. [CrossRef] [PubMed]
Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Xiang, B.; Gao, J.; Jia, Y.-X. Au-catalyzed ring-opening reactions of
2-(1-alkynyl-cyclopropyl) pyridines with nucleophiles. Org. Biomol. Chem. 2015, 13, 4855–4858. [CrossRef]
[PubMed]
Molecules 2016, 21, 332
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
14 of 15
Liu, R.-R.; Cai, Z.-Y.; Lu, C.-J.; Ye, S.-C.; Xiang, B.; Gao, J.; Jia, Y.-X. Indolizine synthesis via Cu-catalyzed
cyclization of 2-(2-enynyl) pyridines with nucleophiles. Org. Chem. Front. 2015, 2, 226–230. [CrossRef]
Liu, R.R.; Lu, C.J.; Zhang, M.D.; Gao, J.R.; Jia, Y.X. Palladium-catalyzed three-component cascade reaction:
Facial access to densely functionalized indolizines. Chem. Eur. J. 2015, 21, 7057–7060. [CrossRef] [PubMed]
Kaloko, J.; Hayford, A. Direct synthesis of monofunctionalized indolizine derivatives bearing alkoxymethyl
substituents at C-3 and their benzofused analogues. Org. Lett. 2005, 7, 4305–4308. [CrossRef] [PubMed]
Chernyak, D.; Skontos, C.; Gevorgyan, V. Two-component approach toward a fully substituted N-fused
pyrrole ring. Org. Lett. 2010, 12, 3242–3245. [CrossRef] [PubMed]
Meng, X.; Liao, P.; Liu, J.; Bi, X. Silver-catalyzed cyclization of 2-pyridyl alkynyl carbinols with isocyanides:
Divergent synthesis of indolizines and pyrroles. Chem. Commun. 2014, 50, 11837–11839. [CrossRef] [PubMed]
Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. Highly efficient synthesis of functionalized indolizines and
indolizinones by copper-catalyzed cycloisomerizations of propargylic pyridines. J. Org. Chem. 2007, 72,
7783–7786. [CrossRef] [PubMed]
Yan, B.; Liu, Y. Gold-catalyzed multicomponent synthesis of aminoindolizines from aldehydes, amines, and
alkynes under solvent-free conditions or in water. Org. Lett. 2007, 9, 4323–4326. [CrossRef] [PubMed]
Seregin, I.V.; Gevorgyan, V. Gold-catalyzed 1,2-migration of silicon, tin, and germanium en route to C-2
substituted fused pyrrole-containing heterocycles. J. Am. Chem. Soc. 2006, 128, 12050–12051. [CrossRef]
[PubMed]
Smith, C.R.; Bunnelle, E.M.; Rhodes, A.J.; Sarpong, R. Pt-catalyzed cyclization/1,2-migration for the synthesis
of indolizines, pyrrolones, and indolizinones. Org. Lett. 2007, 9, 1169–1171. [CrossRef] [PubMed]
Katritzky, A.R.; Qiu, G.; Yang, B.; He, H.-Y. Novel syntheses of indolizines and pyrrolo[2,1-a]isoquinolines
via benzotriazole methodology. J. Org. Chem. 1999, 64, 7618–7621. [CrossRef]
Elender, K.; Riebel, P.; Weber, A.; Sauer, J.R. 1,3-Dipolar cycloaddition reactions of stable bicyclic and
monocyclic azomethine ylides: Kinetic aspects. Tetrahedron 2000, 56, 4261–4265. [CrossRef]
Bora, U.; Saikia, A.; Boruah, R.C. A novel microwave-mediated one-pot synthesis of indolizines via a
three-component reaction. Org. Lett. 2003, 5, 435–438. [CrossRef] [PubMed]
Dinica, R.; Druta, I.; Pettinari, C. The synthesis of substituted 7,71 -bis-indolizines via 1,3-dipolar cycloaddition
under microwave irradiation. Synlett 2000, 1013–1015. [CrossRef]
Dinica, R.M.; Furdui, B.; Ghinea, I.O.; Bahrim, G.; Bonte, S.; Demeunynck, M. Novel one-pot green synthesis
of indolizines biocatalyzed by Candida antartica lipases. Mar. Drugs 2013, 11, 431–439. [CrossRef] [PubMed]
Douglass, J.E.; Tabor, M.W.; Spradling, J.E., III. Effect of 4-substituents on the stability of pyridinium
dicarbethoxymethylides. J. Heterocycl. Chem. 1972, 9, 53–56. [CrossRef]
Georgescu, E.; Caira, M.R.; Georgescu, F.; Draghici, B.; Popa, M.M.; Dumitrascu, F. One-pot, three-component
synthesis of a library of new pyrrolo[1,2-a]quinoline derivatives. Synlett 2009, 1795–1799. [CrossRef]
Shang, Y.; Zhang, M.; Yu, S.; Ju, K.; He, X. New routes synthesis of indolizines via 1,3-dipolar cycloaddition
of pyridiniums and alkynes. Tetrahedron Lett. 2009, 50, 6981–6984. [CrossRef]
Huisgen, R. On the mechanism of 1,3-dipolar cycloadditions. A reply. J. Org. Chem. 1968, 33, 2291–2297.
[CrossRef]
Matsumoto, K.; Hayashi, N.; Ikemi, Y.; Toda, M.; Uchida, T.; Aoyama, Y.; Miyakoshi, Y. Inverse
electron-demand 1,3-dipolar cycloaddition reactions of cyclooctyne with pyridinium bis(methoxycarbonyl)
methylides. J. Het. Chem. 2001, 38, 371–377. [CrossRef]
Shevchenko, V.V.; Zhegalova, N.G.; Borsenko, A.O.; Nikolaev, A.E. On the most powerful chemical traps for
bis(methoxycarbonyl)carbene (2-methoxy-1-(methoxycarbonyl)-2-oxoethylidene). Helv. Chim. Acta 2008, 91,
501–509. [CrossRef]
Sustmann, R. A simple model for substituent effects in cycloaddition reactions. II. The diels-alder reaction.
Tetrahedron Lett. 1971, 12, 2721–2724. [CrossRef]
Sustmann, R. Orbital energy control of cycloaddition reactivity. Pure Appl. Chem. 1974, 40, 569–593.
[CrossRef]
Sandeep, C.; Padmashali, B.; Kulkarni, R.S. Efficient synthesis of indolizines and new imidazo[1,2-a]pyridines
via the expected cyclization of aromatic cycloimmonium ylides with electron deficient alkynes and ethyl
cyanoformate. Tetrahedron Lett. 2013, 54, 6411–6414. [CrossRef]
Molecules 2016, 21, 332
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
15 of 15
Sandeep, C.; Padmashali, B.; Kulkarni, R.S.; Mallikarjuna, S.M.; Siddesh, M.B.; Nagesh, H.K.; Thriveni, K.S.
Synthesis of substituted 5-acetyl-3-benzoylindolizine-1-carboxylate from substituted 2-acetyl pyridinium
bromides. Het. Lett. 2014, 4, 371–376.
Phillips, W.G.; Ratts, K.W. Basicity of n-ylides. J. Org. Chem. 1970, 35, 3144–3147. [CrossRef]
Dega-Szafran, Z.; Schroeder, G.; Szafran, M.; Szwajca, A.; Łeska, B.; Lewandowska, M. Experimental and
quantum chemical evidences for C–H¨ ¨ ¨ N hydrogen bonds involving quaternary pyridinium salts and
pyridinium ylides. J. Mol. Struct. 2000, 555, 31–42. [CrossRef]
Zhang, X.M.; Bordwell, F.G.; Van Der Puy, M.; Fried, H.E. Equilibrium acidities and homolytic bond
dissociation energies of the acidic carbon-hydrogen bonds in N-substituted trimethylammonium and
pyridinium cations. J. Org. Chem. 1993, 58, 3060–3066. [CrossRef]
Le Droumaguet, C.; Wang, C.; Wang, Q. Fluorogenic click reaction. Chem. Soc. Rev. 2010, 39, 1233–1239.
[CrossRef] [PubMed]
Rotaru, A.; Druta, I.; Avram, E.; Danac, R. Synthesis and properties of fluorescent 1,3-substituted mono and
biindolizines. ARKIVOC 2009, xiii, 287–289.
Devaraj, N.K.; Weissleder, R. Biomedical applications of tetrazine cycloadditions. Acc. Chem. Res. 2011, 44,
816–827. [CrossRef] [PubMed]
Saracoglu, N. Recent advances and applications in 1,2,4,5-tetrazine chemistry. Tetrahedron 2007, 63, 4199–4236.
[CrossRef]
Bonte, S.; Ghinea, I.O.; Xuereb, J.-P.; Dinica, R.; Demeunynck, M. Playing with lipases to favor 1,2- versus
1,4-addition of nucleophiles to propiolic ester: Access to activated terminal alkines. Tetrahedron 2013, 69,
5499–5500.
Austin, W.B.; Bilow, N.; Kelleghan, W.J.; Lau, K.S.Y. Facile synthesis fo ethynylated benzoic acid derivatives
and aromatic compounds via ethynyltrimethylsilane. J. Org. Chem. 1981, 46, 4280. [CrossRef]
Allgäuer, D.S.; Mayr, H. One-pot two-step synthesis of 1-(ethoxycarbonyl)indolizines via pyridinium ylides.
Eur. J. Org. Chem. 2013, 2013, 6379–6388. [CrossRef]
Seethalakshmi, T.; Venkatesan, P.; Fronczek, F.R.; Kaliannan, P.; Thamotharan, S. 4-amino-(1-carboxymethyl)
pyridinium chloride. Acta Crystallogr. Sect. E Struct. Rep. Online 2006, 62, o3389–o3390. [CrossRef]
Gundersen, L.-L.; Charnock, C.; Negussie, A.H.; Rise, F.; Teklu, S. Synthesis of indolizine derivatives with
selective antibacterial activity against mycobacterium tuberculosis. Eur. J. Pharm. Sci. 2007, 30, 26–35.
[CrossRef] [PubMed]
Matsumoto, K.; Fujita, H.; Deguchi, Y. Formation of a novel complex between pyridinium
bis(alkoxycarbonyl)methylides and diphenylcyclopropenone; trapping of pyridinium bis(alkoxycarbonyl)
methylide cation radicals. J. Chem. Soc. Chem. Commun. 1978, 817–819. [CrossRef]
Rečnik, S.; Svete, J.; Stanovnik, B. Ring contractions of 4-oxoquinolizine-3-diazonium tetrafluoroborates, by
an aza-Wolff rearrangement, to alkyl indolizine-3-carboxylates. Eur. J. Org. Chem. 2001, 2001, 3705–3709.
[CrossRef]
Soare, M.-L.; Ungureanu, E.-M.; Georgescu, E.; Birzan, L. Synthesis and electrochemical characterization of
substituted indolizine carboxylates. J. Serb. Chem. Soc. 2013, 78, 827–838. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
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