Synthesis of Imidazo[1,2- a]pyridines: Triflic Anhydride-Mediated Annulation of 2 H-Azirines with 2-Chloropyridines

Article abstract of DOI:10.1021/acs.joc.0c02148

The discovery and optimization of a reaction between 2-chloropyridines and 2H-azirines producing imidazo[1,2-a]pyridines is described. The treatment of 2H-azirines with triflic anhydride (Tf2O) forms an electrophilic 1-trifloyl-aziridin-2-yl triflate spec

Full text of DOI:10.1021/acs.joc.0c02148

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Synthesis of Imidazo[1,2‑a]pyridines: Triflic Anhydride-Mediated
Annulation of 2H‑Azirines with 2‑Chloropyridines
†
†
́
́
Frederic Vuillermet, Joanick Bourret, and Guillaume Pelletier*
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ABSTRACT: The discovery and optimization of a reaction
between 2-chloropyridines and 2H-azirines producing imidazo-
[1,2-a]pyridines is described. The treatment of 2H-azirines with
triflic anhydride (Tf2O) forms an electrophilic 1-trifloyl-aziridin-2-
yl triflate species which, when reacted in situ with 2-halopyridines,
generates transient pyridinium salts. These salts were treated in the
same pot with triethylamine (Et3N), leading to the selective
formation of C3-substituted imidazo[1,2-a]pyridines, an hetero-
cyclic moiety commonly found in medicinal chemistry leads and
drugs. Thorough optimization of the activation/cyclization resulted
in yields ranging from 15 to 85% for a variety of substituted
heterocycles.
permutations of the C3-substituents of the imidazo[1,2-
a]pyridine ring can have a profound effect on bioactivity.3
New methods to affect such manipulations become important
in the context of medicinal chemistry as the structure−activity
relationship study around this heterocycle requires convergent
synthetic methodologies for rapid and efficient modification of
all positions.
Correspondingly, many methodologies dedicated to diversi-
fying the imidazo[1,2-a]pyridine scaffold were reported in
recent years.1,4 For instance, C−H functionalization reactions
were specifically developed for the modulation of the C3-
substituents of this heterocycle.5 Strategies aimed at synthesiz-
ing the bicyclic core from simple fragments, and/or
diversifying a pre-existing imidazo[1,2-a]pyridine ring, have
also been recently disclosed.1 However, there is still a need for
convergent synthetic methods toward complex imidazo[1,2-
a]pyridines from commercially available building blocks. In
this context, we disclose herein the rapid assembly of these
bicyclic heterocycles through the combination of 2H-azirines
and 2-halopyridines in the presence of triflic anhydride (Tf2O).
In 2017, the Maulide group reported conditions to
synthesize tetrazolium triflate salts (6) from secondary amides
(5) and alkyl azides (Scheme 1a).6 It is well recognized that
secondary amides can react in the presence of Tf2O and a weak
INTRODUCTION
■
The synthesis and application of the imidazo[1,2-a]pyridine
scaffold has seen considerable advancements in the last
decade.1 This bicyclic heterocycle is frequently encountered
in many approved and commercialized drugs, clinical
candidates, natural products, and functional materials.2 For
example, zolpidem (Ambien, 1), miroprofen (2), soraprazan
(remofuscin, 3), and the more complex antibiotic rifaximin
(xifaxan, 4) all embed the imidazo[1,2-a]pyridine moiety
(Figure 1). This bicycle showcases various positions that can
be modified in order to modulate the physicochemical or
pharmaceutical properties of a given target. Specifically,
Received: September 5, 2020
Figure 1. Examples of commercialized drugs containing the
imidazo[1,2-a]pyridine moiety (highlighted in blue).
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Scheme 1. Maulide’s Conditions to Form Tetrazolium Salts 6 (a) and Extrapolation toward Imidazole 9 (b)
a
base to form highly electrophilic iminium triflates or nitrilium
ions.7 Following such activation, alkyl azides can therefore add
to these electrophiles via formal (3 + 2) cycloadditions to form
a range of substituted tetrazolium triflate salts (6). We were
initially inspired by Maulide’s conditions as we hypothesized
that alkyl azides could be replaced by 1-vinyl azides (or 2H-
azirines) toward the synthesis of 1,2,4-trisubstituted imidazoles
(Scheme 1b). To test this hypothesis, we first treated amide 7
in the presence of 2H-azirine 8a under the reported optimized
conditions [Tf2O, 2-fluoropyridine (2-FPyr), DCM, 0 °C],
expecting to form imidazole 9. Following LCMS monitoring of
the reaction, we observed some residual starting materials (8a
and 7) along with trace amounts of a product with a mass
consistent with 9. Among the products formed, we
unexpectedly identified the imidazo[1,2-a]pyridine 10a (13%
yield).8 This product stems from the reaction between an
equivalent of 8a and an equivalent of the base used in the
reaction (2-FPyr). Intrigued by this result, we further
investigated the possibility to obtain selectively the imidazo-
[1,2-a]pyridine by omitting the addition of the secondary
amide 7 in the activation step while varying the nature of the
base. Interestingly, when 2H-azirine 8a was treated in the
presence of 2-chloropyridine (2-ClPyr) with Tf2O, the C3-
substituted imidazo[1,2-a]pyridine 10a was isolated in 38%
yield (Table 1). This regioselectivity preference for C3 is
complementary to a closely related transformation reported in
2014 by the Adimurthy group, where C2-substituted imidazo-
[1,2-a]pyridines were formed selectively when pyridines
reacted with 1-vinyl azides in the presence of CuI.9
Encouraged by these results, we decided to delve further
into optimizing these conditions toward 10a.
Table 1. Optimization of Reaction Conditions
solvent
(M)
temp.
b
entry
1
(°C)
quench
yield 10a (%)
c
DCM
DCM
DCM
DCM
DME
−78 to rt NaHCO3
−78 to rt NaHCO3
−78 to rt NaHCO3
−20 to rt NaHCO3
−20 to rt NaHCO3
−20 to rt NaHCO3
−20 to rt NaHCO3
−20 to rt NaHCO3
−20 to rt NaOH 1 M
−20 to rt citric acid 10%
−20 to rt sat. NaCl
−20 to rt Et3N (2.0 equiv)
−20 to rt Bu4NOH (2.0 equiv)
−20 to rt Et3N (2.0 equiv)
−20 to rt Et3N (2.0 equiv)
35 (38)
d
2
3
29
40
20
0
20
34
42
41
7
e
4
5
6
7
Tol.
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
f
8
f
9
f
10
f
11
0
f
c
12
93 (80)
f
13
22
82
74
fg
14 ,
fh
15 ,
a
Reaction conditions: 8a (1.0 equiv), Tf2O (1.2 equiv), 2-
chloropyridine 11a (2.0 equiv), −78 °C to rt, 16 h, then NaHCO3
sat. aq. Refers to H NMR yield using 1,3,5-trimethoxybenzene as
the internal standard. Isolated yield in parentheses. Tf2O (1.5
equiv). 2-ClPyr (5.0 equiv). Anhydrous Na2SO4 was added. 2-FPyr
b
1
c
d
e
f
g
h
(2.0 equiv) used instead of 2-ClPyr. 2-BrPyr (2.0 equiv) used instead
of 2-ClPyr.
RESULTS AND DISCUSSION
(entries 4−7).7 The temperature was also adjusted at −20 °C
to avoid solidification of CHCl3 (and some other solvents
screened).10 During optimization, we observed that the
reactions were sensitive to the presence of residual water.
This led us to the use of strictly anhydrous solvents and
desiccants (see Scheme 3 for more details). Consequently,
addition of an external desiccant such as 3 Å MS or anhydrous
Na2SO4 to CHCl3 gave a cleaner reaction profile (42% vs 34%,
entries 8 vs 7). Furthermore, we saw a sharp difference in yield
for 10a when the reaction is quenched with a basic solution
versus an acidic aqueous medium (entries 8−11). While
■
To capitalize on the initial findings, we set out to identify
parameters that could improve the efficiency of the reaction
(Table 1). First, we varied the amount of Tf2O and base while
fixing 2H-azirine 8a and 2-chloropyridine 11a as the reactants
(entries 1−3). These modifications did not improve the
reaction profile as we only observed slightly better yields of
10a if a large excess of 2-ClPyr is employed (entry 3).
Modulating the solvent showed that the reaction is best
performed in chlorinated solvents, in this case with CHCl3,
similar to what is known in Tf2O-mediated amide activations
B
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Table 2. Substrate Scope of Imidazo[1,2-a]pyridines: Variation of the 2-Chloropyridine
a
b
Isolated yields. The reaction was treated with Et3N (2.0 equiv) for 16 h at 80 °C.
moderate yields were obtained when the reactions are
quenched with either aqueous saturated NaHCO3 or 1 M
NaOH (42 and 41%, respectively, entries 8−9), the desired
the scope of this activation-cyclization sequence with respect to
the 2-chloropyridine component (11a−11t, see the Reagents
section in the Supporting Information) (Table 2). Methyl
substitution at position 5 (76%, 10b), position 4 (77%, 10c),
and position 3 (50%, 10d) of the 2-chloropyridine were well
tolerated. 2-Chloropyridines substituted with halogens (Cl, Br,
I, and F) gave clean conversions of 8a and among the best
performing reactions (70 to 85% yields, entries 10f−i).
Imidazo[1,2-a]pyridines substituted with a nitrile (10e,
47%), an ester (75%, 10j), trifluoromethyl (55%, 10k),
trifluoromethoxy (49%, 10l), and nitro (45%, 10m) were
also formed in satisfactory yields after treatment with Et3N.
The reactions giving 4-phenyl-imidazo[1,2-a]pyridine (10n),
imidazo[1,2-b]isoquinoline (10o), and imidazo[2,1-a]-
isoquinoline (10p) were found to be sluggish and lower yields
for the heterocycles were obtained (45, 31 and 18%). This
methodology can also be performed with 2-chloropyrimidine,
1
product was barely observed in the crude H NMR of similar
reactions quenched with citric acid (10% wt) or saturated
aqueous NaCl solutions. These results prompted us to instead
quench the reaction with anhydrous organic bases (entries 12−
13). Notably, in the presence of 2.0 equiv of anhydrous Et3N,
we saw complete and clean conversion to 10a (93% yield by
1H NMR) and obtained 80% yield of the desired compound
after purification. Substitution of 2-ClPyr by either 2-FPyr
(82%, entry 14) or 2-BrPyr (74%, entry 15) was still
productive toward 10a, but to a lesser extent than with 2-
ClPyr.
With a set of reaction conditions identified which provided
high yields for the formation of 10a, we set out to demonstrate
C
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2,5-dichloropyrazine, and 3-chloropyridazine providing a quick
access to other poly-nitrogen-containing bicyclic heterocycles
(10q−s, 28−51%). When the reaction was first performed with
2-chloroquinoline, no conversion to the desired heterocycle
10t was observed. However, after a quick reoptimization of the
reaction conditions for this substrate,10 an encouraging 15%
yield was obtained for 10t when the reaction is heated at 80 °C
for 16 h after the addition of Et3N.
products. In these cases, we observed possible formation of
pyridinium intermediates by LCMS analysis of the crude
mixtures (analogous to 19g, vide infra). Potentially, these
pyridinium species might be too stable to undergo base-
mediated cyclization toward the desired compounds. In
addition, it was found that 2-chloropyridines containing an
aldehyde (11x), a boronic ester (11y), or a primary alcohol
(11z) also failed to generate desired imidazo-pyridine
products, which could be due to either the instability of the
obtained products or to competition with 2H-azirines for Tf2O
activation.
During the study of this reaction, we found that certain 2-
halopyridines were not productive and gave no conversion
toward the desired imidazo[1,2-a]pyridines (Figure 2). For
A variety of 2H-azirines (8) were then investigated toward
the formation of imidazo[1,2-a]pyridines (14) using our
optimized conditions with 2-chloropyridine 11a (Table 3).
These 2H-azirines were synthesized from their corresponding
styrenes 12 (and 1-vinyl azides 13) following literature
protocols (see Experimental Section).11,12 Generally, we
found that most of the 2H-azirines (8) tested under the
optimized conditions gave moderate yields of the correspond-
ing imidazo[1,2-a]pyridines (14). Aryl-substituted 2H-azirines
containing a halogen at position 2, 3, or 4 of the phenyl ring
were all tolerated (14b−14e) as well as electron-rich and
electron-poor aryl functionalities (14f−14k). Notably,
imidazo[1,2-a]pyridines substituted with an alkyl azide or
pinacol boronic ester were effectively obtained, which could
Figure 2. 2-Chloropyridines which were unproductive under the
optimized reaction conditions.
example, electron-rich pyridines such as 11u and 11v, as well
as 2-chloropyridines possessing substitution at the 6-position
such as 2-chloro-6-methylpyridine (11w), failed to give desired
Table 3. Substrate Scope of Imidazo[1,2-a]pyridines: Variation of the 2H-Azirine
a
Isolated yields.
D
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provide synthetic handles for further functionalization through
click chemistry or transition-metal-catalyzed cross-couplings
(14m, 14n). In the counterpart, a few 2H-azirines substituted
on the methylene moiety were tested under the optimized
conditions, but they did not provide substantial amount of
their corresponding imidazo[1,2-a]pyridines.
To gain more insight into the reaction, we selected a few
control experiments. An initial reaction between the 2H-azirine
8a and a slight excess of Tf2O in anhydrous CDCl3 was
initiated without the inclusion of any 2-halopyridine derivative
(Scheme 2). A rapid and complete reaction was observed to
this, we revisited the reaction between 2H-azirine 8a and 3-
bromo-2-chloropyridine 11g as we previously observed that a
precipitate was gradually formed with this pyridine prior to
Et3N addition (Scheme 4). Performing this reaction in CDCl3
Scheme 4. Interception of a Pyridinium Salt 19g and
Subsequent Formation of 10g
Scheme 2. Formation of a Transient 1-Triflyl-aziridin-2-yl
N-Triflate 16
without inclusion of Na2SO4 or triethylamine led to the
formation of a white suspension, which could be isolated by
filtration. Characterization of this reaction intermediate by
LCMS and NMR in THF-d8 led to its assignment as bench
stable pyridinium-aziridine salt 19g (96% yield). The structure
1
of this compound was supported by H NMR wherein the
take place to form a transient and reactive intermediate in
solution. Attempts to isolate this intermediate were un-
successful as it rapidly hydrolyzed under air and moisture.
However, this intermediate was sufficiently stable in solution to
be characterized in situ. We hypothesized that the 2H-azirine
8a is initially activated through nucleophilic attack of the
nitrogen lone pair onto the highly electrophilic Tf2O giving rise
to an N-triflyl azirinium triflate salt (15). This iminium ion
would then equilibrate to the more stable and neutral 1-triflyl-
aziridine methylene signal is again observed as a pair of
doublets with small J coupling constants of 1.5 Hz observed at
4.71 and 4.51 ppm, respectively. Importantly, independent
treatment of this isolated pyridinium salt in CHCl3 with 2.0
equiv of Et3N procured 10g in 77% yield. This result supports
the hypothesis that pyridinium salts such as 19g could be
productive intermediates in the reaction mechanism toward
the formation of imidazo[1,2-a]pyridines.
With the information above, our proposed mechanism for
the formation of imidazo[1,2-a]pyridines 10 and 14 is shown
in Scheme 5. First, 2H-azirines 8 are chemoselectively activated
by Tf2O in the presence of 2-chloropyridines15 to provide
electrophilic 1-triflyl-aziridin-2-yl N-triflates 16 (in equilibrium
with 15). The selective activation of azirines over 2-
chloropyridines is supported by previous observations from
the Movassaghi group that 2-chloropyridine and Tf2O does not
provide a stable and viable N-triflyl pyridinium salt in
chlorinated solvents, even at −78 °C.16 Intermediate 15 then
reacts with a 2-chloropyridine derivatives to provide stable
pyridinium salts such as 19. From this intermediate, two
pathways are possible: pathway A (in blue) involves a [1,3]-
sigmatropic rearrangement of 19, which leads to a bicyclic salt
such as 20a. Neutralization/tautomerization of 20a is possible
via addition of a base such as Et3N to provide 21. The second
pathway (B, in red) involves a base-mediated ring-opening of
19 to form a zwitterionic intermediate 20b, which is followed
by intramolecular SNAr to form 21. Elimination of the N-
triflate group with concomitant rearomatization procures the
observed heterocycles 10 and 14. We were unable to isolate
intermediates such as 20a,b−22; however, an analogous
reaction was already reported by the Yoo group,17 wherein
similar N-quinolinium zwitterion dipoles could cyclize to form
the corresponding imidazo[1,2-a]quinolines.
To support the applicability of the developed method, we
targeted the synthesis of a highly potent Mnk1/Mnk2 inhibitor
25 disclosed in 2018 by the Nacro group (Scheme 6).18
Compound 25 is originally prepared via commercially available
6-bromoimidazo[1,2-a]pyrazine in five steps. We thought that
such a compound could also be easily accessed using our
reported conditions starting from 2H-azirine 8l, synthesized in
three steps from 4-acetoxystyrene, and 2,5-dichloropyrazine
(11r). Applying our optimized conditions on a 2.95 mmol
scale of 8l, we were delighted to isolate the corresponding
1
aziridin-2-yl N-triflate (16); its structure is supported by H
NMR (Supporting Information, pages S8−S10).10 The
methylene singlet at 1.83 ppm in CDCl3 of the starting
material 8a is now observed as a pair of doublets at 3.67 and
3.57 ppm, respectively, after activation. Both protons are now
diastereotopic because of the formation of a chiral center α- to
the aryl ring and N-Tf moiety. Moreover, both doublets have a
small J coupling constants of 2.4 Hz, suggesting that the
strained aziridine 3-membered ring is conserved.13
1
Compound 18 was also observed by LCMS and H NMR
when the reaction solvent was not anhydrous or when some
water was added after the activation step of the reaction
(Scheme 3). We suspect that the formation of this ketone
Scheme 3. Formation of N-Triflyl Acetophenone Derivative
18
arose from hydrolysis of the activated intermediate 15
observed previously (see Scheme 2). In the presence of
water, the iminium ion could be substituted by water forming
an unstable hemiaminal intermediate 17 which could ring-
open to the observed N-triflyl α-amino acetophenone 18.14
Moreover, 1H NMR signals from this ketone (minor
1
contaminant) can be seen in the H NMR of 16 alluded to
previously. The formation of 18 also supports the activation of
8a with Tf2O via the nitrogen lone pair.
Following these results, we investigated whether formation
of stable pyridinium salts was occurring in this reaction. To do
E
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Scheme 5. Proposed Mechanism for the Formation of Imidazo[1,2-a]pyridines 10 and 14
Scheme 6. Synthesis of the Highly Potent Mnk1/Mnk2 Inhibitor
from commercial suppliers and used without further purification.
Spectra were processed using the automatic phasing and polynomial
baseline correction features of the software. Spectral data are reported
as follows: chemical shift {multiplicity [singlet (s), broad singlet (br
s), doublet (d), triplet (t), quartet (q), sextuplet (sex), multiplet (m),
apparent (app), doublet of doublets (dd), doublet of doublet of
doublets (ddd), doublet of triplets (dt)], coupling constant,
integration}. Chemical shifts are reported in parts per million (δ),
and coupling constants are reported in hertz. 1H resonances are
referenced to solvent residual peaks for CDCl3 (7.26 ppm), DMSO-d6
(2.50 ppm), or THF-d8 (3.58 ppm or 1.73 ppm).19 Routine 13C{1H}-
NMR spectra were recorded on Brucker or Oxford 400 or 500 MHz
spectrometer with protons fully decoupled. 13C{1H} Resonances are
reported in parts per million relative to solvent residual peaks for
CDCl3 (77.2 ppm), DMSO-d6 (39.52 ppm), or THF-d8 (67.57 or
25.37 ppm).19 Structural assignments were made with additional
information from gCOSY, gHSQC, and HMBC 2D NMR experi-
ments (for 10a, see the Supporting Information). Routine 19F-NMR
spectra were recorded on Oxford or Brucker 400 or 500 MHz
spectrometer. 19F Resonances are reported in ppm relative to 0.1%
1,1,1-trifluorotoluene added as the internal standard, with literature
resonance peak at −63.72 ppm.
imidazo[1,2-a]pyrazine 23 in 56% yield. This reaction sets the
stage for a Suzuki cross-coupling between commercially
available boronic ester 24 and 23 to procure inhibitor 25 in
77%. Considering that aqueous basic conditions are employed
in the Suzuki coupling, we were pleased to observe complete
hydrolysis of the aryl acetate in this coupling to directly
provide the desired target compound.
CONCLUSIONS
■
General conditions to synthesize C3-substituted imidazo[1,2-
a]pyridines were found. The reaction was optimized to give up
to 93% NMR yield, and 85% isolated yield for the desired
bicyclic heterocycles. The scope of the reaction with respect to
2-chloropyridine and 2H-azirines was investigated, giving over
30 examples of imidazo[1,2-a]pyridines with various sub-
stitution patterns. We were able to identify and characterize
key intermediates of the reaction. These studies support the
implication of transient pyridinium salts in the mechanism of
the reaction as they were shown to proceed toward the
formation of the desired heterocycles under basic conditions.
Extension of the concepts presented in this study to the
synthesis of other heterocycles is currently under investigation.
High-resolution liquid chromatography−mass spectrometry (MS)
was performed by the DMPK group at Paraza Pharma Inc on a Q
Exactive Plus Hybrid Quadrupole-Orbitrap Mass Spectrometer using
a XBridge BEH C18 2.1 × 30 mm, 2.5 μm column set at 50 °C. An
ESI ionization source was used with the following parameters:
resolution of 140,000, AGC target of 3.00 × 106, maximum IT 25 ms,
scan range of 100−700 m/z, and positive/negative polarity. Direct
injection high-resolution MS (HRMS) analysis was performed by
EXPERIMENTAL SECTION
General Information. Routine H NMR spectra were recorded
on 400, or 500 MHz spectrometers (Oxford or Bruker) at ambient
temperature. NMR solvents, d-chloroform (CDCl3), d6-dimethylsulf-
oxide (DMSO-d6), and d8-tetrahydrofuran (THF-d8), were purchased
■
1
́
́
́
Centre Regional de Spectrometrie de Masse de l’Universite de
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́
Montreal on a Agilent TOF 6224 with an ESI ionization source using
the mixture was stirred for 2 h and the solvent was removed with a
stream of air. The crude dibromide was then directly used in the next
step without purification.
positive polarity and a scan range of 100−3200 m/z. The HPLC-UV/
MS instrumentation for crude analysis consisted of a Waters Alliance
2695 with a column heater coupled with a ZQ 4000 mass
spectrometer. The MS was equipped with an electrospray ionization
(ESI) source and used in scan mode (100−1200 amu, source
temperature: 150 °C) for both positive and negative ionization. The
HPLC was equipped with a Waters photodiode array detector (PDA)
2998 (range used: 195−320 nm). The analytical method was
developed on a XBridge C18 column (3.5 μm particle size, 4.6 ×
30 mm) with a 10 mM buffer (ammonium formate pH 3.8 or
ammonium bicarbonate pH 10)A % and acetonitrileB % as the
mobile phase. A flow rate of 3 mL/min at 25 °C was set and the
following gradient was used: 5% B isocratic for 0.2 min, 5%−100% B
in 1.8 min, 100% B for 1 min. Fourier-transform infrared spectroscopy
(FTIR) spectal acquisition was performed at Neomed Institute on a
Nicolet 6700 FTIR from Thermo Scientific equipped with ATR
module, model Smart iTR. Scan range: 4000−450 cm−1.
Substitution and Elimination. The dibrominated product (1.0
equiv) was dissolved in DMSO (0.67 M). Solid sodium azide (1.5
equiv) was added portionwise into the solution (over 45 min) at rt.
Over the course of the reaction, we usually noted that the mixture
became a thick suspension/gel. The reaction was stirred overnight at
rt. The elimination step was then triggered by addition of a solution of
NaOH (1.0 equiv) in deionized water (0.5 M). Stirring was continued
1
at room temperature, and the reaction was monitored by H NMR.
Upon completion, the mixture was poured into an aqueous solution of
2% wt of sodium bicarbonate, and the reaction was diluted with DCM
until two layers were obtained. The aqueous solution was extracted
with DCM (2×), and the organic layers were combined. The extracts
were washed with water (4×), and the solvent was removed in vacuo
to give the crude product. Purification was done by flash column
chromatography (heptanes/EtOAc) to yield the corresponding 1-
vinyl azides 13.
Analytical thin-layer chromatography (TLC) was performed using
60 Å Silica Gel F254 precoated plates (0.25 mm thickness). TLC
plates were visualized by irradiation with a UV lamp and, if necessary,
revealed using chemical stains cerium ammonium molybdenate
(CAM), potassium permanganate (KMnO4), or iodine on silica gel.
Normal-phase manual column chromatography was performed using
60 Å silica gel (32−62 μm) with an appropriate mobile phase
composition and gradient. Normal-phase automated column
chromatography was performed using a Biotage Isolera, Yamazen,
or Isco Rf flash purification systems equipped with a 10, 25, 50, 100,
or 340 g SNAP Ultra or Isco Gold columns.
Thermolysis of Vinyl Azides toward 2H-Azirines (Procedure
C, Adapted from the Literature).12 CAUTION: Heating of
organic azides may cause explosion, always work behind a blast shield
in a well ventilated area and with appropriate personal protective
equipment. To a round-bottom flask equipped with a reflux condenser
was added 1-vinyl azide 13 (1.0 equiv) along with toluene (0.2 M).
The solution was heated at 115−120 °C (at reflux) in an oil bath for 2
1
h (or until the thermolysis was complete as observed by H NMR
analysis of an aliquot of the reaction in CDCl3). The reaction was
then cooled to rt, and the solvent was evaporated in vacuo. The crude
product was used as is or purified by flash column chromatography
(heptanes/EtOAc) to yield the corresponding 2H-azirines (8). Note:
Because the 2H-azirines were found to decompose if stored at room
temperature, it is appropriate to store them in a freezer at −20 °C
over long periods of time (>24 h). We observed minimal
decomposition of 2H-azirines at −20 °C if stored neat over multiple
months.
Synthesis of 1-Vinylazide from Treatment of the Corre-
sponding Styrenes with ICl/t-BuOK (Procedure A, Adapted
from the Literature).11 CAUTION: Iodine azide (IN3) is generated
in situ in this reaction and should always be kept in solution. IN3 is a
known toxic and explosive compound. Manipulation of IN3 should be
performed under a well ventilated area with appropriate personal
protective equipment.Organic azides are potentially explosive
substances that can decompose with the slight input of energy from
external sources, always work behind a blast shield. To a stirred
solution of ICl (1.50 equiv) in anhydrous MeCN (2.6 M) at −20 °C
(iPrOH/H2O, 1:1 with dry ice bath) was added solid sodium azide
(2.5 equiv) portionwise at −20 °C while keeping the internal
temperature of the reaction below −10 °C. The reaction was stirred
for 1 h at −20 °C and then the reaction mixture was warmed to 0 °C
(ice/water bath). A solution of styrene 12 (1.0 equiv) in anhydrous
MeCN (2.6 M) was then added dropwise. The reaction was stirred
for 1 h at 0 °C before being quenched by dropwise addition of 10% wt
aqueous solution of Na2S2O3 under stirring until color changed to a
yellow or translucent solution. The mixture was partitioned between
diethyl ether and water (1:1) while being transferred to an extraction
funnel. The organic layer was separated and washed with a 10% wt
aqueous solution of Na2S2O3 (1×) and then brine (2×). The organic
solution was then dried over anhydrous Na2SO4 and filtered over a
sintered funnel, and the filtrate was evaporated to dryness (rotary
evaporator bath temperature ≤25 °C). 1H NMR of the crude showed
complete conversion of the styrene to the saturated addition product.
The crude residue was dissolved in diethyl ether (0.3 M), and solution
was cooled to 0 °C. KOtBu (1.5 equiv) was added in one portion.
The reaction became black, and a solid precipitated out of the
mixture. The suspension was stirred for 1 h while warming to 0 °C to
rt. The crude was filtered over a silica gel pad with a layer of Celite on
top. The pad was rinsed using diethyl ether, and the filtrate was
concentrated in vacuo. The residual vinyl azide (13) was generally
clean enough by 1H NMR to continue to the next step without
purification.
3-(4-Bromophenyl)-2H-azirine 8a.20 Synthesized according to
procedures A and C. Purified using a gradient of 100% heptanes to
40% EtOAc in 60% heptanes, 5.7 g (43.7 mmol scale), 67% over three
steps. Obtained as an orange solid. The product corresponds to
literature characterization. 1H NMR (400 MHz, CDCl3): δ 7.79−7.76
(m, 2H), 7.73−7.70 (m, 2H), 1.81 (s, 2H).
3-(3-Bromophenyl)-2H-azirine 8b. Synthesized according to
procedures A and C. Purified using a gradient of 100% heptanes to
40% EtOAc in 60% heptanes, 1.9 g (15.6 mmol scale), 63% over three
steps. Obtained as a yellow oil. 1H NMR (500 MHz, CDCl3): δ 8.08−
7.98 (m, 1H), 7.89−7.81 (m, 1H), 7.71 (ddd, J = 8.0, 2.0, 1.1 Hz,
1H), 7.49−7.38 (m, 1H), 1.81 (s, 2H). 13C{1H} NMR (126 MHz,
CDCl3): δ 165.4, 135.9, 132.5, 130.8, 128.1, 127.6, 123.2, 20.3. IR ν:
3049, 2978, 2894, 1742, 1591, 1565, 1473, 1418, 1310, 1291 cm−1.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C8H7BrN, 195.9757; found, 195.9756.
3-(2-Bromophenyl)-2H-azirine 8c.21 Synthesized according to
procedures A and C. The product was found to be pure enough to
use without flash chromatography, 2.74 g (16.4 mmol scale), 86%
over three steps. Obtained as a yellow solid. The product corresponds
1
to literature characterization. H NMR (400 MHz, CDCl3): δ 7.86−
7.83 (m, 1H), 7.75−7.72 (m, 1H), 7.53−7.41 (m, 2H), 1.89 (s, 2H).
3-(3-Chlorophenyl)-2H-azirine 8d. Synthesized according to
procedures A and C. Purified using a gradient of 100% heptanes to
40% EtOAc in 60% heptanes, 2.2 g (21.6 mmol scale), 63% over three
1
steps. Obtained as an orange oil. H NMR (500 MHz, DMSO-d6): δ
7.96 (ddd, J = 2.0, 1.5, 0.4 Hz, 1H), 7.90−7.88 (m, 1H), 7.77 (ddd, J
= 8.1, 2.2, 1.1 Hz, 1H), 7.70−7.67 (m, 1H), 1.77 (s, 2H). 13C{1H}
NMR (126 MHz, DMSO-d6): δ 165.2, 134.2, 133.2, 131.6, 128.9,
127.9, 127.1, 19.7. IR ν: 3051, 2980, 1743, 1569, 1475, 1456, 1475,
1456, 1424, 1412, 1312, 1292 cm−1. HRMS (ESI/Q-Exactive
Orbitrap) m/z: [M + H]+ calcd for C8H7ClN, 152.0262; found,
152.0261.
Synthesis of 1-Vinyl Azides from Dibromination of the
Corresponding Styrenes (Procedure B, Adapted from the
Literature).12 Bromination of Alkenes and Styrenes. Bromine (1.0
equiv) in CCl4 (0.7 M) was added to a stirred and cooled (water bath,
15−20 °C) solution of the corresponding styrene (1.0 equiv) in CCl4
(0.7 M) in a round-bottom flask. After the addition was completed,
G
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Article
3-(2-Chlorophenyl)-2H-azirine 8e.22 Synthesized according to
procedures A and C. The product was found to be pure enough to
use without flash chromatography, 2.87 g (21.6 mmol scale), 87%
over three steps. Obtained as an orange oil. The product corresponds
δ 7.93 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 4.47 (s, 2H), 1.81
(s, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 165.5, 140.5, 130.0,
128.6, 125.4, 54.5, 19.8. IR ν: 3047, 2978, 2888, 2208, 1735, 1605,
1417, 1279, 1264, 1208 cm−1. HRMS (ESI/Q-TOF) m/z: [M + H]+
calcd for C9H9N4, 173.0822; found, 173.0818.
1
to literature characterization. H NMR (400 MHz, CDCl3): δ 7.86
(dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.55 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.52
(dt, J = 7.2 Hz, 1.6 Hz, 1H), 7.46 (dt, J = 7.2 Hz, 1.6 Hz, 1H), 1.85 (s,
2H).
3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-
azirine 8n.24 Synthesized according to procedures B and C. Purified
using a gradient of 100% heptanes to 40% EtOAc in 60% heptanes,
410 mg (4.35 mmol scale), 44% over four steps. Obtained as an
orange solid. The product corresponds to literature characterization.
1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 2H), 7.89 (d, J =
3-(2-Fluorophenyl)-2H-azirine 8f. Synthesized according to
procedures A and C. The product was found to be pure enough to
use without flash chromatography, 2.85 g (24.6 mmol scale), 85%
1
over three steps. Obtained as an orange solid. H NMR (400 MHz,
8.0 Hz, 2H), 1.80 (s, 2H), 1.37 (s, 12H).
CDCl3): δ 7.88−7.84 (m, 1H), 7.62−7.59 (m, 1H), 7.38−7.35 (m,
1H), 7.29−7.27 (m, 1H), 1.80 (s, 2H). 13C{1H} NMR (126 MHz,
CDCl3): δ 162.3, 161.8 (d, 1J = 260.8 Hz, JC−F), 134.9 (d, 3J = 8.8 Hz,
General Procedure for the Addition of 2-Chloropyridine
Derivatives 11 to Activated 8a (Procedure D). 3-(4-Bromo-
phenyl)-2H-azirine (8a, 100 mg, 0.512 mmol, 1.0 equiv), sodium
sulfate (100 mg), and the 2-chloropyridine derivative (11) (1.02
mmol, 2.0 equiv) were loaded in a flame-dried, nitrogen-flushed 2−5
mL Biotage microwave tube under a nitrogen atmosphere. Anhydrous
chloroform (2.6 mL, 0.2 M) was added, and the mixture was stirred
until complete dissolution of the 2H-azirine. The solution was cooled
to −20 °C in a water/isopropanol and dry ice bath (1:1).
Trifluoromethanesulfonic anhydride (Tf2O) (172.9 mg, 103 μL,
0.612 mmol, 1.2 equiv) was added dropwise to the solution, which
became dark brown. The mixture was left to stir for an hour at −20
°C and then for another hour at room temperature. The reaction was
then treated with anhydrous triethylamine (103.2 mg, 142 μL, 1.02
mmol, 2.0 equiv), and the course of the reaction was monitored by
LCMS. Upon full conversion of the pyridinium salt to the desired
product (for each example, reaction time with Et3N is indicated in the
characterization section), the mixture was then transferred to a 125
mL extraction funnel and extracted with DCM (2 × 40 mL) and
aqueous sodium hydroxide (1 M, 10 mL). The organic extracts were
combined, dried with sodium sulfate, and filtered over a sintered
funnel, and the filtrate was evaporated under vacuo. The crude
product was then purified by flash chromatography (heptanes/EtOAc,
25 g SNAP Ultra) to yield the desired compound 10.
J
C−F), 131.4 (d, 4J = 1.3 Hz, JC−F), 124.8 (d, 3J = 3.8 Hz, JC−F), 116.6
(d, 2J = 20.2 Hz, JC−F), 114.4 (d, 2J = 11.3 Hz, JC−F), 18.7. 19F NMR
(376 MHz, CDCl3): δ −64.0 (s). IR ν: 3303, 3065, 2103, 1612, 1579,
1485, 1451, 1212 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M
+ H]+ calcd for C8H7FN, 136.0557; found, 136.0556.
3-(4-Methoxyphenyl)-2H-azirine 8g.22 Synthesized according to
procedures A and C. The product was found to be pure enough to use
without flash chromatography, 2.85 g (22.4 mmol scale), 86% over
three steps. Obtained as an orange solid. The product corresponds to
literature characterization. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J
= 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H), 1.74 (s, 2H).
Methyl 4-(2H-Azirin-3-yl)benzoate 8h.23 Synthesized according to
procedures B and C. Purified using a gradient of 100% heptanes to
40% EtOAc in 60% heptanes, 56 mg (4.62 mmol scale), 22% over
four steps. Obtained as an orange solid. The product corresponds to
literature characterization. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J
= 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 4.00 (s, 3H), 1.88 (s, 2H).
3-(4-(tert-Butyl)phenyl)-2H-azirine 8i.23 Synthesized according to
procedures A and C. The product was found to be pure enough to use
without flash chromatography, 2.75 g (17.4 mmol scale), 91% over
three steps. Obtained as an orange oil. The product corresponds to
literature characterization. 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J
= 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 1.78 (s, 2H), 1.39 (s, 9H).
3-(3-(Trifluoromethyl)phenyl)-2H-azirine 8j. Synthesized accord-
ing to procedures A and C. The product was found to be pure enough
to use without flash chromatography, 4.55 g (24.6 mmol scale), 88%
3-(4-Bromophenyl)imidazo[1,2-a]pyridine 10a.9 The product
was isolated following general procedure D using 2-chloropyridine
11a. The reaction was stirred with Et3N for 10 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Orange oil
(110 mg, 80% Yield). The product corresponds to literature
1
over three steps. Obtained as an orange oil. H NMR (400 MHz,
1
characterization. H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 7.0
CDCl3): δ 8.16 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.5 Hz,
1H), 7.72 (dd, J = 8.0, 7.5 Hz, 1H), 1.88 (s, 2H). 13C{1H} NMR (126
MHz, DMSO-d6): δ 165.2, 132.8, 130.7, 130.2 (q, 2J = 32.8 Hz, JC−F),
129.6 (q, 3J = 4.0 Hz, JC−F), 126.1, 125.7 (q, 3J = 3.5 Hz, JC−F), 123.6
(q, 1J = 273.4 Hz, JC−F), 19.7. 19F NMR (376 MHz, CDCl3): δ −64.1
(s). IR ν: 3076, 2877, 1653, 1611, 1489, 1447, 1419, 1325 cm−1.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C9H7F3N, 186.0525; found, 186.0525.
Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.67−7.59 (m, 2H), 7.47−7.39 (m,
2H), 7.30−7.19 (m, 1H), 6.85 (td, J = 6.9, 1.0 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ 146.0, 132.5, 132.3, 129.5, 128.0, 124.9,
124.6, 123.2, 122.2, 118.2, 113.1. HRMS (ESI/Q-Exactive Orbitrap)
m/z: [M + H]+ calcd for C13H10BrN2, 273.0022; found, 273.0024.
3-(4-Bromophenyl)-6-methylimidazo[1,2-a]pyridine 10b.24 The
product was isolated following general procedure D using 2-chloro-5-
methylpyridine 11b. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Brown oil (111 mg, 76% Yield). The product corresponds to
3-(Naphthalen-2-yl)-2H-azirine 8k.22 Synthesized according to
procedures B and C. Purified using a gradient of 100% heptanes to
50% EtOAc in 50% heptanes, 876 mg (12.0 mmol scale), 60% over 4
steps. Obtained as an orange solid. The product corresponds to
1
literature characterization. H NMR (400 MHz, CDCl3): δ 8.04 (s,
1
1H), 7.65 (d, J = 6.6 Hz, 2H), 7.64 (s, 1H) 7.59 (d, J = 9.2 Hz, 1H),
7.42 (d, J = 8.2 Hz, 2H), 7.09 (dd, J = 9.2, 1.6 Hz, 1H), 2.32 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 145.3, 132.5, 132.1, 129.5,
128.2, 128.0, 124.3, 122.7, 122.1, 120.8, 117.5, 18.4. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C14H12BrN2, 287.0179;
found, 287.0178.
3-(4-Bromophenyl)-7-methylimidazo[1,2-a]pyridine 10c. The
product was isolated following general procedure D using 2-chloro-
4-methylpyridine 11c. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Red oil (113 mg, 77% Yield). 1H NMR (400 MHz, CDCl3): δ
8.16 (d, J = 7.1 Hz, 1H), 7.64 (s, 1H), 7.61 (d, J = 3.2 Hz, 2H), 7.50−
7.41 (m, 3H), 6.71 (dd, J = 7.1, 1.5 Hz, 1H), 2.45 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 146.3, 136.6, 132.6, 131.4, 129.5, 128.1,
124.3, 122.7, 122.2, 116.3, 116.0, 21.4. IR ν: 3084, 2920, 2854, 1648,
1535, 1494, 1469, 1336, 1304, 1225, 1189, 1138 cm−1. HRMS (ESI/
literature characterization. H NMR (400 MHz, CDCl3): δ 8.36 (s,
1H), 8.03−7.98 (m, 3H), 7.92 (d, J = 8.0 Hz, 1H), 7.61−7.50 (m,
2H), 1.89 (s, 2H).
3-(4-Acetoxyphenyl)-2H-azirine 8l. Synthesized according to
procedures B and C. Purified using a gradient of 100% heptanes to
40% EtOAc in 60% heptanes, 1.87 g (30.8 mmol scale), 35% over four
steps. Obtained as an orange solid. 1H NMR (500 MHz, DMSO-d6):
δ 8.05−7.89 (m, 2H), 7.50−7.37 (m, 2H), 2.32 (s, 3H), 1.73 (s, 2H).
13C{1H} NMR (126 MHz, DMSO-d6): δ 169.1, 164.6, 154.2, 130.9,
123.3, 122.6, 21.0, 19.2. IR ν: 3495, 3047, 2975, 2887, 1751, 1599,
1502, 1415, 1368, 1191 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/
z: [M + H]+ calcd for C10H10NO2, 176.0706; found, 176.0706.
3-(4-(Azidomethyl)phenyl)-2H-azirine 8m.23 Synthesized accord-
ing to procedures B and C. Purified using a gradient of 100% heptanes
to 40% EtOAc in 60% heptanes, 121 mg (12 mmol scale), 9% over
four steps. Obtained as an orange solid. 1H NMR (400 MHz, CDCl3):
H
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3
Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C14H12BrN2,
287.0179; found, 287.0178.
= 236.9 Hz, JC−F), 144.4, 132.9 (d, J = 2.5 Hz, JC−F), 132.6, 129.4,
4
2
129.3, 128.0, 126.2 (d, J = 2.0 Hz, JC−F), 122.4, 115.5 (d, J = 25.4
3-(4-Bromophenyl)-8-methylimidazo[1,2-a]pyridine 10d.25 The
product was isolated following general procedure D using 2-chloro-3-
methylpyridine 11d. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Yellow solid (73.8 mg, 50% Yield). The product corresponds
to literature characterization. 1H NMR (400 MHz, CDCl3): δ 8.16 (d,
J = 6.9 Hz, 1H), 7.69 (s, 1H), 7.67−7.62 (m, 2H), 7.46−7.40 (m,
2H), 7.09−7.03 (m, 1H), 6.78 (t, J = 6.9 Hz, 1H), 2.65 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 146.5, 132.6, 131.6, 129.7,
Hz, JC−F), 107.7 (d, J = 41.6 Hz, JC−F), 17.2 (d, J = 1.2 Hz, JC−F).
2
4
19F NMR (471 MHz, CDCl3): δ −75.7 (s). IR ν: 3095, 3059, 2988,
2926, 1645, 1615, 1557, 1494, 1469, 1394, 1382, 1340, 1309, 1284,
1265 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C14H11BrFN2, 305.0084; found, 305.0083.
Ethyl 3-(4-Bromophenyl)imidazo[1,2-a]pyridine-8-carboxylate
10j. The product was isolated following general procedure D using
ethyl 2-chloronicotinate 11j. The reaction was stirred with Et3N for
10 min. Brine was used instead of sodium hydroxide 1 M in the work-
up procedure to avoid ester hydrolysis. Purified using a gradient of
30% EtOAc in 70% heptanes to 100% EtOAc. Dark orange solid (132
mg, 75%). 1H NMR (500 MHz, CDCl3): δ 8.41 (dd, J = 8.0, 2.0 Hz,
1H), 7.98 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.67 (d, J = 6.5 Hz, 2H),
7.42 (d, J = 6.5 Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H), 4.55 (q, J = 7.0 Hz,
2H), 1.47 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
164.4, 143.4, 133.8, 132.6, 129.9, 128.9, 127.7, 126.9, 125.1, 122.8,
120.9, 111.8, 61.8, 14.4. IR ν: 3050, 2984, 2929, 1721, 1531, 1489,
1472, 1265, 1201 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M
+ H]+ calcd for C16H14BrN2O2, 345.0233; found, 345.0235.
3-(4-Bromophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine
10k. The product was isolated following general procedure D using 2-
chloro-4-trifluoromethylpyridine 11k. The reaction was stirred with
Et3N for 10 min. Purified using a gradient of 30% EtOAc in 70%
heptanes to 100% EtOAc. Light brown solid (78 mg, 55%). 1H NMR
(500 MHz, CDCl3): δ 8.36 (dt, J = 7.0, 1.0 Hz, 1H), 8.02 (dt, J = 1.9,
1.0 Hz, 1H), 7.84 (s, 1H), 7.71−7.67 (m, 2H), 7.46−7.42 (m, 2H),
7.02 (dd, J = 7.3, 1.8 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
144.2, 134.5, 132.8, 129.7, 127.2, 126.5 (q, 2J = 34.0 Hz, JC−F), 126.1,
128.3, 128.1, 125.2, 124.0, 122.3, 121.3, 113.3, 17.2. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C14H12BrN2, 287.0179;
found, 287.0178.
3-(4-Bromophenyl)imidazo[1,2-a]pyridine-7-carbonitrile 10e.
The product was isolated following general procedure D using 2-
chloro-4-cyanopyridine 11e. The reaction was stirred with Et3N for 10
min. Purified using a gradient of 30% EtOAc in 70% heptanes to
100% EtOAc. Brown solid (72.2 mg, 47% Yield). 1H NMR (500
MHz, CDCl3): δ 8.33 (dd, J = 7.2, 0.8 Hz, 1H), 8.11−8.07 (m, 1H),
7.90 (s, 1H), 7.73−7.67 (m, 2H), 7.46−7.40 (m, 2H), 6.98 (dd, J =
7.2, 1.6 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 144.1, 135.8,
133.0, 129.8, 127.0, 126.8, 124.8, 124.1, 123.6, 117.6, 113.2, 107.2. IR
ν: 3076, 3060, 2230, 1487, 1472, 1457, 1402, 1332, 1310, 1296, 1278,
1184 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C14H9BrN3, 297.9975; found, 297.9973.
3-(4-Bromophenyl)-8-chloroimidazo[1,2-a]pyridine 10f. The
product was isolated following general procedure D using 2,3-
dichloropyridine 11f. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Brown solid (119 mg, 76%). 1H NMR (500 MHz, CDCl3): δ
8.20 (dd, J = 6.9, 1.0 Hz, 1H), 7.74 (s, 1H), 7.69−7.63 (m, 2H),
7.45−7.39 (m, 2H), 7.30 (dd, J = 7.3, 1.0 Hz, 1H), 6.79 (t, J = 7.1 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 143.7, 133.2, 132.7, 129.8,
127.8, 126.5, 124.3, 123.7, 122.9, 122.1, 112.7. IR ν: 3091, 3041,
3026, 1537, 1520, 1491, 1473, 1347, 1306, 1292, 1219 cm−1. HRMS
(ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C13H9BrClN2,
306.9632; found, 306.9633.
8-Bromo-3-(4-bromophenyl)imidazo[1,2-a]pyridine 10g. The
product was isolated following general procedure D using 3-bromo-
2-chloropyridine 11g. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Brown solid (153 mg, 85%). 1H NMR (500 MHz, CDCl3): δ
8.24 (dd, J = 6.9, 0.9 Hz, 1H), 7.76 (s, 1H), 7.68−7.64 (m, 2H), 7.50
(dd, J = 7.2, 0.9 Hz, 1H), 7.45−7.40 (m, 2H), 6.73 (t, J = 7.1 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 144.2, 133.2, 132.8, 129.8,
127.9, 127.2, 126.6, 122.9, 122.7, 113.1, 112.6. IR ν: 3084, 3038,
1535, 1511, 1486, 1472, 1343, 1303, 1291 cm−1. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C13H9Br2N2, 350.9127;
found, 350.9126.
3-(4-Bromophenyl)-8-iodoimidazo[1,2-a]pyridine 10h. The
product was isolated following general procedure D using 2-chloro-
3-iodopyridine 11h. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Brown solid (167 mg, 82%). 1H NMR (500 MHz, CDCl3): δ
8.25 (dd, J = 6.9, 1.0 Hz, 1H), 7.76 (s, 1H), 7.73 (dd, J = 7.1, 1.0 Hz,
1H), 7.67−7.64 (m, 2H), 7.43−7.40 (m, 2H), 6.60 (t, J = 7.0 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 145.5, 134.3, 132.8 (2),
129.8, 127.9, 126.7, 123.6, 122.9, 113.9, 85.0. IR ν: 3071, 3035, 2999,
1534, 1502, 1483, 1472, 1433, 1400, 1341, 1292, 1212 cm−1. HRMS
(ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C13H9BrIN2,
398.8989; found, 398.8990.
1
3
124.0, 123.2 (q, J = 272.2 Hz, JC−F), 123.1, 116.4 (q, J = 5.0 Hz,
3
J
C−F), 108.9 (q, J = 2.5 Hz, JC−F). 19F NMR (471 MHz, CDCl3): δ
−62.37 (s). IR ν: 3099, 3075, 1493, 1469, 1346, 1315, 1303, 1266,
1252 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C14H9BrF3N2, 340.9896; found, 340.9897.
3-(4-Bromophenyl)-6-(trifluoromethoxy)imidazo[1,2-a]pyridine
10l. The product was isolated following general procedure D using 2-
chloro-5-trifluoromethoxypyridine 11l. The reaction was stirred with
Et3N for 36 h. Purified using a gradient of 30% EtOAc in 70%
heptanes to 100% EtOAc. Light brown solid (89 mg, 49%). 1H NMR
(500 MHz, CDCl3): δ 8.28 (dd, J = 1.5, 0.7 Hz, 1H), 7.77 (s, 1H),
7.72 (d, J = 0.8 Hz, 1H), 7.71−7.68 (m, 2H), 7.44−7.40 (m, 2H),
7.20 (ddd, J = 9.8, 2.1, 1.0 Hz, 1H). 13C{1H} NMR (126 MHz,
3
CDCl3): δ 144.6, 138.7 (q, J = 2.5 Hz, JC−F), 134.2, 132.8, 129.4,
1
127.4, 126.0, 122.9, 120.6 (q, J = 258.3 Hz, JC−F), 120.4, 118.9,
116.9. 19F NMR (471 MHz, CDCl3): δ −58.35 (s). IR ν: 3100, 1536,
1501, 1476, 1243, 1201, 1159 cm−1. HRMS (ESI/Q-Exactive
Orbitrap) m/z: [M + H]+ calcd for C14H9BrF3N2O, 356.9845;
found, 356.9846.
3-(4-Bromophenyl)-6-nitroimidazo[1,2-a]pyridine 10m. The
product was isolated following general procedure D using 2-chloro-
5-nitropyridine 11m. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Brown solid (73.7 mg, 45%). 1H NMR (500 MHz, CDCl3): δ
9.33 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 9.8, 2.1 Hz, 1H), 7.86 (s, 1H),
7.77−7.73 (m, 3H), 7.45 (d, J = 8.3 Hz, 2H). 13C{1H} NMR (126
MHz, CDCl3): δ 146.0, 137.9, 135.8, 133.1, 129.8, 127.4, 126.3,
123.8, 123.6, 118.6, 118.1. IR ν: 3581, 3102, 2922, 2851, 1637, 1547,
1517, 1502, 1471, 1364, 1349, 1237, 1289 cm−1. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C13H9BrN3O2, 317.9873;
found, 317.9854.
3-(4-Bromophenyl)-7-phenylimidazo[1,2-a]pyridine 10n. The
product was isolated following general procedure D using 2-chloro-
4-phenylpyridine 11n. The reaction was stirred with Et3N for 10 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Orange solid (80.1 mg, 45%). 1H NMR (400 MHz, CDCl3):
δ 8.34 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.69−7.66 (m,
4H), 7.52−7.46 (m, 4H), 7.42 (t, J = 7.3 Hz, 1H), 7.15 (dd, J = 7.2,
1.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 146.6, 145.5,
138.3, 137.9, 133.0, 132.5, 129.4, 129.1, 128.4, 128.0, 126.8, 123.1,
3-(4-Bromophenyl)-6-fluoro-8-methylimidazo[1,2-a]pyridine
10i. The product was isolated following general procedure D using 2-
chloro-5-fluoro-3-picoline 11i. The reaction was stirred with Et3N for
10 min. Purified using a gradient of 30% EtOAc in 70% heptanes to
1
100% EtOAc. Brown powder (109 mg, 70%). H NMR (500 MHz,
CDCl3): δ 8.00 (ddd, J = 4.2, 2.3, 0.6 Hz, 1H), 7.62 (s, 1H), 7.58−
7.56 (m, 2H), 7.34−7.32 (m, 2H), 6.90 (ddd, J = 8.5, 2.2, 1.1 Hz,
1H), 2.59 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 153.7 (d, 1J
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122.3, 114.8, 113.0. IR ν: 3053, 2921, 1642, 1590, 1496, 1484, 1475,
1341, 1310, 1294, 1234, 1171 cm−1. HRMS (ESI/Q-Exactive
Orbitrap) m/z: [M + H]+ calcd for C19H14BrN2, 349.0335; found,
349.0337.
13C{1H} NMR (126 MHz, CDCl3): δ 145.3, 133.9, 133.5, 132.2,
131.7, 130.9, 129.5, 128.1, 127.6, 127.1, 124.9, 124.8, 123.3, 117.6,
117.0. IR ν: 3066, 2922, 2851, 1611, 1546, 1474, 1445, 1380, 1301
cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C17H12BrN2, 323.0179; found, 323.0179.
3-(4-Bromophenyl)imidazo[1,2-b]isoquinoline 10o. The product
was isolated following general procedure D using 1-chloroisoquinoline
11o. The reaction was stirred with Et3N for 12 h. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Orange oil
General Procedure for the Addition of 2-Chloropyridine
11a to Various Activated 2H-Azirines 8 (Procedure E). 2H-
azirine (8, 1.0 mmol, 1.0 equiv), sodium sulfate (100 mg for 100 mg
of 8), and 2-chloropyridine (11a) (227 mg, 189 μL, 2.0 mmol, 2.0
equiv) were loaded in a flame-dried, nitrogen-flushed 2−5 mL Biotage
microwave tube under a nitrogen atmosphere. Anhydrous chloroform
(5.0 mL, 0.2 M) was added, and the mixture was stirred until
complete dissolution of the azirine. The solution was cooled to −20
°C in a water/isopropanol and dry ice bath. Trifluormethanesulfonic
anhydride (338 mg, 202 μL, 1.2 mmol, 1.2 equiv) was added
dropwise to the solution, which became dark brown. The mixture was
left to stir for an hour at −20 °C and then for another hour at room
temperature. The reaction was then treated with anhydrous
triethylamine (202 mg, 278 μL, 2.0 mmol, 2.0 equiv), and the course
of the reaction monitored by LCMS. Upon full conversion of the
pyridinium salt to the desired product (for each example, reaction
time with Et3N is indicated in the characterization section), the
mixture was then transferred to a 125 mL extraction funnel and
extracted with DCM (2×) and aqueous sodium hydroxide (1 M). The
organic extracts were combined and dried with sodium sulfate, filtered
over a sintered funnel, and the filtrate was evaporated under vacuo.
The crude product was then purified by flash chromatography
(heptanes/EtOAc, 25 g SNAP Ultra) to yield the desired compound
14.
1
(51.7 mg, 31%). H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.38
(s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.14 (t, J = 7.2 Hz, 1H), 8.07 (d, J =
8.3 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.38 (d, J = 8.7
Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H). 13C{1H} NMR (126 MHz,
CDCl3): δ 155.4, 139.9, 139.5, 139.2, 138.6, 133.7, 132.4, 131.7,
130.5, 127.0, 126.9, 126.8, 123.3, 120.2, 120.1. IR ν: 3075, 3030,
1618, 1593, 1491, 1396, 1289, 1235, 1192 cm−1. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C17H12BrN2, 323.0179;
found, 323.0177.
3-(4-Bromophenyl)imidazo[2,1-a]isoquinoline 10p. The product
was isolated following general procedure D using 3-chloroisoquinoline
11p. The reaction was stirred with Et3N for 12 h. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown oil
(30.1 mg, 18%). 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 8.0 Hz,
1H), 8.02 (d, J = 7.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.70−7.63
(m, 4H), 7.60 (dd, J = 7.5, 1.1 Hz, 1H), 7.49−7.42 (m, 2H), 7.08 (d,
J = 7.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 144.1, 132.6,
130.5, 130.0, 129.5, 128.6 (2), 128.3, 127.0, 126.9, 124.2, 123.6,
122.5, 120.9, 113.7. IR ν: 3048, 2924, 1625, 1477, 1449, 1329, 1290
cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C17H12BrN2, 323.0179; found, 323.0179.
3-(4-Bromophenyl)imidazo[1,2-a]pyrimidine 10q. The product
was isolated following general procedure D using 2-chloropyrimidine
11q. The reaction was stirred with Et3N for 1 h. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown solid
3-(3-Bromophenyl)imidazo[1,2-a]pyridine 14b.27 The product
was isolated following general procedure E (on 1.0 mmol of 8b). The
reaction was stirred with Et3N for 2 h 30 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Orange
viscous liquid (191 mg, 70%). The product corresponds to literature
characterization. 1H NMR (500 MHz, CDCl3): δ 8.32 (dt, J = 7.0, 1.2
Hz, 1H), 7.72−7.69 (m, 3H), 7.55 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H),
7.50 (ddd, J = 7.7, 1.6, 1.1 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.27−
7.22 (m, 1H), 6.87 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3): δ 146.2, 132.8, 131.2 (2), 130.8 (2), 126.5, 124.9,
124.3, 123.3, 123.2, 118.3, 113.1. HRMS (ESI/Q-Exactive Orbitrap)
m/z: [M + H]+ calcd for C13H10BrN2, 273.0022; found, 273.0022.
3-(2-Bromophenyl)imidazo[1,2-a]pyridine 14c.28 The product
was isolated following general procedure E (on 1.0 mmol of 8c).
The reaction was stirred with Et3N for 5 h. Purified using a gradient of
30% EtOAc in 70% heptanes to 100% EtOAc. Orange solid (136 mg,
50%). The product corresponds to literature characterization. 1H
NMR (500 MHz, CDCl3): δ 7.81 (dt, J = 6.9, 1.2 Hz, 1H), 7.78−7.75
(m, 1H), 7.73−7.70 (m, 2H), 7.47−7.43 (m, 2H), 7.38−7.33 (m,
1H), 7.25 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.82 (td, J = 6.8, 1.2 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 145.7, 133.6, 133.5, 133.3,
130.8, 130.3, 127.9, 125.2, 124.8, 124.6, 124.5, 118.1, 112.4. HRMS
(ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C13H10BrN2,
273.0022; found, 273.0023.
1
(72 mg, 51%). H NMR (500 MHz, CDCl3): δ 8.61−8.57 (m, 2H),
7.89 (s, 1H), 7.69−7.65 (m, 2H), 7.44−7.40 (m, 2H), 6.93 (dd, J =
6.7, 4.2 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 149.9, 149.3,
134.2, 132.9, 131.1, 129.5, 127.3, 123.3, 122.9, 109.3. IR ν: 3082,
3062, 3049, 3035, 2928, 1613, 1513, 1490, 1465, 1422, 1280 cm−1.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C12H9BrN3, 273.9975; found, 273.9975.
3-(4-Bromophenyl)-6-chloroimidazo[1,2-a]pyrazine 10r. The
product was isolated following general procedure D using 2,5-
dichloropyrazine 11r. The reaction was stirred with Et3N for 15 min.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
1
EtOAc. Brown solid. (81.0 mg, 51%). H NMR (400 MHz, CDCl3):
δ 8.98 (d, J = 1.3 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.92 (s, 1H),
7.75−7.70 (m, 2H), 7.46−7.42 (m, 2H). 13C{1H} NMR (126 MHz,
CDCl3): δ 143.2, 140.6, 136.3, 135.9, 133.1, 129.5, 126.7, 126.3,
123.9, 114.1. IR ν: 3105, 3049, 2919, 2850, 1604, 1468, 1415, 1312,
1140 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C12H8BrClN3, 307.9585; found, 307.9586.
3-(4-Bromophenyl)-6-chloroimidazo[1,2-b]pyridazine 10s.26
The product was isolated following general procedure D using 3-
chloropyridazine 11s. The reaction was stirred with Et3N for 1 h.
Purified using a gradient of 30% EtOAc in 70% heptanes to 100%
EtOAc. Yellow solid. (40 mg, 28%). The product corresponds to
3-(3-Chlorophenyl)imidazo[1,2-a]pyridine 14d.28b,29 The prod-
uct was isolated following general procedure E (on 1.0 mmol of 8d).
The reaction was stirred with Et3N for 2 h 30 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Dark orange
viscous liquid (165 mg, 69%). The product corresponds to literature
characterization. 1H NMR (500 MHz, CDCl3): δ 8.31 (dt, J = 7.0, 1.2
Hz, 1H), 7.71 (s, 1H), 7.68 (dt, J = 9.1, 1.1 Hz, 1H), 7.55 (ddd, J =
2.1, 1.3, 0.8 Hz, 1H), 7.45−7.43 (m, 2H), 7.41−7.36 (m, 1H), 7.23
(ddd, J = 9.1, 6.7, 1.2 Hz, 1H), 6.85 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3): δ 146.4, 135.2, 133.0, 131.1, 130.5, 128.2,
127.8, 126.0, 124.7, 124.4, 123.2, 118.4, 113.0. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C13H10ClN2, 229.0527;
found, 229.0527.
1
literature characterization. H NMR (500 MHz, CDCl3): δ 8.06 (s,
1H), 7.97 (d, J = 9.4 Hz, 1H), 7.95−7.90 (m, 2H), 7.67−7.60 (m,
2H), 7.11 (d, J = 9.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
147.2, 139.0, 133.7, 132.2, 128.4, 127.6, 126.9 (2), 122.6, 118.6.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C12H8BrClN3, 307.9585; found, 307.9586.
1-(4-Bromophenyl)imidazo[1,2-a]quinoline 10t. The product was
isolated following general procedure D (on 0.25 mmol of 8a) with 2-
chloroquinoline 11t, but after Et3N (2.0 equiv.) was added, the
reaction was heated in an oil bath at 80 °C for 16 h. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Orange
3-(2-Chlorophenyl)imidazo[1,2-a]pyridine 14e.28,29 The product
was isolated following general procedure E (on 1.0 mmol of 8e). The
reaction was stirred with Et3N for 4 h 30 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown solid
1
solid (12.3 mg, 15%). H NMR (500 MHz, CDCl3): δ 7.80 (dd, J =
7.8, 1.5 Hz, 1H), 7.68−7.64 (m, 2H), 7.61−7.53 (m, 3H), 7.49 (s,
1H), 7.43−7.38 (m, 3H), 7.32 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H).
J
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4
(170 mg, 74%). The product corresponds to literature character-
ization. H NMR (500 MHz, CDCl3): δ 7.83 (dt, J = 6.9, 1.2 Hz,
= 32.6 Hz, JC−F), 131.3 (q, J = 1.2 Hz, JC−F), 130.3, 130.0, 125.1,
125.0 (q, 3J = 7.7 Hz, JC−F), 124.7 (q, 3J = 3.8 Hz, JC−F), 124.4, 123.9
1
1
1H), 7.72−7.69 (m, 2H), 7.59−7.56 (m, 1H), 7.49−7.46 (m, 1H),
7.41 (dd, J = 7.5, 1.8 Hz, 2H), 7.24 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H),
6.82 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
145.9, 134.7, 133.7, 132.8, 130.3, 130.2, 128.2, 127.2, 124.5, 124.4,
122.9, 118.0, 112.3. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M +
H]+ calcd for C13H10ClN2, 229.0527; found, 229.0527.
(q, J = 273.0 Hz, JC−F), 123.2, 118.6, 113.4. 19F NMR (471 MHz,
CDCl3): δ −63.28 (s). HRMS (ESI/Q-Exactive Orbitrap) m/z: [M +
H]+ calcd for C14H10F3N2, 263.0791; found, 263.0787.
3-(Naphthalen-2-yl)imidazo[1,2-a]pyridine 14k.27 The product
was isolated following general procedure E (on 0.6 mmol of 8k). The
reaction was stirred with Et3N for 1 h 30 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown
viscous oil (110 mg, 75%). The product corresponds to literature
characterization. 1H NMR (500 MHz, CDCl3): δ 8.44 (dt, J = 7.0, 1.2
Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.92−
7.88 (m, 2H), 7.81 (s, 1H), 7.73 (dt, J = 9.1, 1.1 Hz, 1H), 7.66 (dd, J
= 8.4, 1.8 Hz, 1H), 7.58−7.52 (m, 2H), 7.24 (ddd, J = 8.6, 6.7, 1.2
Hz, 1H), 6.86 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3): δ 146.2, 133.7, 133.0, 132.7, 129.2, 128.1, 128.0, 127.0 (2),
126.7, 126.6, 125.9 (2), 124.8, 123.6, 118.3, 113.0. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C17H13N2, 245.1073;
found, 245.1071.
3-(2-Fluorophenyl)imidazo[1,2-a]pyridine 14f.28a,b,29a,b,30 The
product was isolated following general procedure E (on 1.0 mmol
of 8f). The reaction was stirred with Et3N for 10 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown solid
(154 mg, 73%). The product corresponds to literature character-
1
ization. H NMR (500 MHz, CDCl3): δ 8.03 (ddt, J = 6.9, 3.1, 1.1
Hz, 1H), 7.76 (s, 1H), 7.73 (dt, J = 9.1, 1.1 Hz, 1H), 7.52 (td, J = 7.4,
1.7 Hz, 1H), 7.49−7.43 (m, 1H), 7.32−7.29 (m, 1H), 7.29−7.27 (m,
1H), 7.27−7.24 (m, 1H), 6.87 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H}
1
NMR (126 MHz, CDCl3): δ 159.9 (d, J = 249.5 Hz, JC−F), 146.0,
133.2, 131.4 (d, 4J = 3.2 Hz, JC−F), 130.6 (d, 3J = 8.2 Hz, JC−F), 125.0,
124.9 (d, 3J = 3.5 Hz, JC−F), 124.5 (d, 3J = 4.5 Hz, JC−F), 120.3, 117.9,
4-(Imidazo[1,2-a]pyridin-3-yl)phenyl Acetate 14l. The product
was isolated following general procedure E (on 1.0 mmol of 8l). The
reaction was stirred with Et3N for 16 h. Brine was used instead of
sodium hydroxide 1 M in the work-up procedure to avoid ester
hydrolysis. Purified using a gradient of 30% EtOAc in 70% heptanes
2
2
116.9 (d, J = 15.2 Hz, JC−F), 116.3 (d, J = 21.5 Hz, JC−F), 112.7.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C13H10FN2, 213.0823; found, 213.0820.
3-(4-Methoxyphenyl)imidazo[1,2-a]pyridine 14g.27 The product
was isolated following general procedure E (on 1.0 mmol of 8g). The
reaction was stirred with Et3N for 1 h 30 min. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown solid
(120 mg, 54%). The product corresponds to literature character-
1
to 100% EtOAc. Yellow solid (167 mg, 66%). H NMR (400 MHz,
CDCl3): δ 8.34 (d, J = 7.0 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.72 (s,
1H), 7.58 (d, J = 8.6 Hz, 2H), 7.35 (dd, J = 8.9, 7.0 Hz, 1H), 7.31−
7.27 (m, 2H), 6.94 (app t, J = 6.7 Hz, 1H), 2.36 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 169.5, 151.0, 145.3, 130.8, 129.6, 126.3,
125.9, 125.3, 123.7, 122.8, 117.8, 113.6, 21.3. IR ν: 3097, 2805, 2670,
1613, 1527, 1498, 1438, 1363, 1265, 1225 cm−1. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C15H13N2O2, 253.0972;
found, 253.0968.
3-(4-(Azidomethyl)phenyl)imidazo[1,2-a]pyridine 14m. The
product was isolated following general procedure E (on 0.283
mmol of 8m). The reaction was stirred with Et3N for 16 h. Purified
using a gradient of 30% EtOAc in 70% heptanes to 100% EtOAc.
Brown solid (50 mg, 71%). 1H NMR (500 MHz, CDCl3): δ 8.34 (dt,
J = 7.0, 1.2 Hz, 1H), 7.72 (s, 1H), 7.70 (dt, J = 9.1, 1.1 Hz, 1H),
7.61−7.57 (m, 2H), 7.50−7.46 (m, 2H), 7.24 (ddd, J = 9.2, 6.7, 1.2
Hz, 1H), 6.85 (td, J = 6.8, 1.2 Hz, 1H), 4.43 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3): δ 146.2, 135.7, 132.4, 129.3, 129.2, 128.6, 125.3,
124.9, 123.5, 118.3, 113.1, 54.6. IR ν: 2941, 2885, 2090, 1610, 1500,
1353, 1313, 1274 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M
+ H]+ calcd for C14H12N5, 250.1087; found, 250.1083.
3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
imidazo[1,2-a]pyridine 14n. The product was isolated following
general procedure E (on 1.0 mmol of 8n). The reaction was stirred
with Et3N for 1 h 30 min. Purified using a gradient of 30% EtOAc in
70% heptanes to 100% EtOAc. White solid. (165 mg, 52%). 1H NMR
(500 MHz, CDCl3): δ 8.38 (dt, J = 7.0, 1.2 Hz, 1H), 7.97−7.94 (m,
2H), 7.74 (s, 1H), 7.70 (dt, J = 9.1, 1.1 Hz, 1H), 7.60−7.57 (m, 2H),
7.23 (ddd, J = 9.1, 6.7, 1.2 Hz, 1H), 6.84 (td, J = 6.8, 1.2 Hz, 1H),
1.37 (s, 12H). 13C{1H} NMR (126 MHz, CDCl3): δ 146.3, 135.8 (2),
132.7, 132.0, 127.1, 125.9, 124.8, 123.6, 118.4, 113.0, 84.2, 25.0. IR ν:
2980, 2928, 1607, 1485, 1359, 1324, 1290 cm−1. HRMS (ESI/Q-
Exactive Orbitrap) m/z: [M + H]+ calcd for C19H22BN2O2, 321.1769;
found, 321.1761.
Experimental Procedure for the Formation of N-(2-(4-
Bromophenyl)-2-oxoethyl)-1,1,1-trifluoromethane Sulfona-
mide (18) (Scheme 3). 3-(4-Bromophenyl)-2H-azirine (8a, 100
mg, 0.512 mmol, 1.0 equiv) and sodium sulfate (100 mg) were
charged in a flame-dried, nitrogen-flushed 2−5 mL Biotage microwave
tube under a nitrogen atmosphere. Anhydrous deuterated chloroform-
d (2.6 mL, 0.2 M) was added, and the mixture was stirred until
complete dissolution of the 2H-azirine. The solution was cooled to
−20 °C in a water/isopropanol and dry ice bath (1:1).
Trifluoromethanesulfonic anhydride (Tf2O) (172.9 mg, 103 μL,
0.612 mmol, 1.2 equiv) was added dropwise to the solution, which
became dark brown. The reaction was immediately quenched by
1
ization. H NMR (500 MHz, CDCl3): δ 8.25 (dt, J = 7.0, 1.2 Hz,
1H), 7.68 (dt, J = 9.1, 1.1 Hz, 1H), 7.63 (s, 1H), 7.49−7.45 (m, 2H),
7.19 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.08−7.03 (m, 2H), 6.80 (td, J =
6.8, 1.2 Hz, 1H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
159.7, 145.6, 131.7, 129.7, 125.6, 124.2, 123.3, 121.4, 118.1, 114.7,
112.5, 55.4. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C14H13N2O, 225.1023; found, 225.1020.
Methyl 4-(Imidazo[1,2-a]pyridin-3-yl)benzoate 14h.29b,31 The
product was isolated following general procedure E (on 1.0 mmol
of 8h). The reaction was stirred with Et3N for 16 h. Brine was used
instead of sodium hydroxide 1 M in the work-up procedure to avoid
ester hydrolysis. Purified using a gradient of 30% EtOAc in 70%
heptanes to 100% EtOAc. Beige solid (140 mg, 55%). The product
corresponds to literature characterization. 1H NMR (500 MHz,
CDCl3): δ 8.40 (dt, J = 7.0, 1.1 Hz, 1H), 8.21−8.15 (m, 2H), 7.79 (s,
1H), 7.71 (dt, J = 9.1, 1.1 Hz, 1H), 7.67−7.64 (m, 2H), 7.25 (ddd, J =
9.1, 6.7, 1.2 Hz, 1H), 6.88 (td, J = 6.8, 1.2 Hz, 1H), 3.96 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3): δ 166.7, 146.8, 133.9, 133.6,
130.7, 129.6, 127.4, 125.1, 125.0, 123.5, 118.6, 113.3, 52.4. HRMS
(ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C15H13N2O2,
253.0972; found, 253.0969.
3-(4-(tert-Butyl)phenyl)imidazo[1,2-a]pyridine 14i.27,32 The
product was isolated following general procedure E (on 1.0 mmol
of 8i). The reaction was stirred with Et3N for 16 h. Purified using a
gradient of 30% EtOAc in 70% heptanes to 100% EtOAc. Brown
solid. (135 mg, 54%). The product corresponds to literature
1
characterization. H NMR (500 MHz, CDCl3): δ 8.35 (dt, J = 7.0,
1.2 Hz, 1H), 7.69 (dt, J = 9.1, 1.1 Hz, 1H), 7.68 (s, 1H), 7.56−7.53
(m, 2H), 7.51−7.48 (m, 2H), 7.21 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H),
6.81 (td, J = 6.8, 1.2 Hz, 1H), 1.38 (s, 9H). 13C{1H} NMR (126
MHz, CDCl3): δ 151.6, 145.9, 132.0, 128.0, 126.3 (2), 125.9, 124.5,
123.7, 118.2, 112.7, 34.9, 31.4. HRMS (ESI/Q-Exactive Orbitrap) m/
z: [M + H]+ calcd for C17H19N2, 251.1543; found, 251.1540.
3-(3-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridine 14j.29,33
The product was isolated following general procedure E (on 1.0
mmol of 8j). The reaction was stirred with Et3N for 16 h. Purified
using a gradient of 30% EtOAc in 70% heptanes to 100% EtOAc.
Brown viscous liquid (158 mg, 60%). The product corresponds to
literature characterization. 1H NMR (500 MHz, CDCl3): δ 8.30 (dt, J
= 7.0, 1.1 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.76−7.72 (m, 2H),
7.70−7.63 (m, 2H), 7.28−7.24 (m, 1H), 6.88 (td, J = 6.8, 1.2 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3): δ 146.6, 133.1, 132.0 (q, 2J
K
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Article
addition of water (1 mL), and the reaction was warmed to rt over 30
min. The mixture was then transferred to a 60 mL extraction funnel
and extracted with DCM (2 × 30 mL) and brine (20 mL). The
organic extracts were combined, dried with sodium sulfate, and
filtered over a sintered funnel, and the filtrate was evaporated under
vacuo. The crude product was then purified by flash chromatography
using a 50 g SNAP Ultra column (100% heptanes to 30% EtOAc in
70% heptanes over 30 CV) to yield the desired compound 1814 (125
and dry ice bath. Freshly distilled trifluormethanesulfonic anhydride
(997 mg, 595 μL, 3.53 mmol, 1.2 equiv) was added dropwise to the
solution, which became dark brown. The mixture was left to stir for an
hour at −20 °C and then for another hour at room temperature. The
reaction was then treated with anhydrous triethylamine (599 mg,
0.825 mL, 5.89 mmol, 2.0 equiv), and the course of the reaction was
monitored by LCMS. Upon full conversion of the pyridinium salt to
the desired product (1 h), the mixture was then transferred to a 125
mL extraction funnel and extracted with DCM (2 × 30 mL) and brine
(20 mL). The organic extracts were combined, dried with sodium
sulfate, and filtered over a sintered funnel, and the filtrate was
evaporated under vacuo. The crude product was then purified by flash
chromatography using a 50 g SNAP Ultra column (100% heptanes to
50% EtOAc in 50% heptanes over 30 CV) to yield the desired
1
mg, 71%) as a yellow solid. H NMR (400 MHz, CDCl3): δ 7.82−
7.79 (m, 2H), 7.71−7.67 (m, 2H), 6.01 (br s, 1H), 4.73 (d, J = 1.0
Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 190.3, 132.7, 131.9,
1
130.5, 129.4, 119.6 (q, J = 321.3 Hz, JC−F), 49.4. 19F NMR (471
MHz, CDCl3): δ −76.64 (s). IR ν: 3240, 1691, 1589, 1397, 1368,
1318 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd
for C9H8BrF3NO3S, 345.9355; found, 345.9351.
1
compound 23 (475 mg, 56%) as a dark brown solid. H NMR (400
MHz, CDCl3): δ 8.98 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 1.2 Hz, 1H),
7.90 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 2.36
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 169.2, 151.4, 142.8,
140.1, 135.9, 135.7, 129.2, 126.8, 124.7, 123.1, 114.0, 21.1. IR ν:
3120, 3048, 1745, 1604, 1490, 1476, 1365, 1326, 1220 cm−1. HRMS
(ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for C14H11ClN3O2,
288.0535; found, 288.0532.
Experimental Procedure for the Formation of 3-Bromo-1-
(2-(4-bromophenyl)-1-((trifluoromethyl)sulfonyl)aziridin-2-
yl)-2-chloropyridin-1-ium (19g) (Scheme 4). 3-(4-Bromophen-
yl)-2H-azirine (8a, 100 mg, 0.512 mmol, 1.0 equiv) and 3-bromo-2-
chloropyridine (195 mg, 1.024 mmol, 2.0 equiv) were charged in a
flame-dried, nitrogen-flushed 2−5 mL Biotage microwave tube under
a nitrogen atmosphere. Anhydrous deuterated chloroform-d (2.6 mL,
0.2 M) was added, and the mixture was stirred until complete
dissolution of the azirine. The solution was cooled to −20 °C in a
water/isopropanol and dry ice bath. Trifluoromethanesulfonic
anhydride (Tf2O) (172.9 mg, 103 μL, 0.612 mmol, 1.2 equiv) was
added dropwise to the solution, which became dark brown. The
solution was stirred at −20 °C for 1 h and at room temperature for 1
h. During that time, a light brown solid precipitated out of the
reaction. The solid was then filtered on a Buchner funnel, and the
solid was washed with CDCl3 (2 × 2 mL). The solid was recuperated
and dried under vacuo to obtain the desired pyridinium salt 19g as a
beige solid (328 mg, 96%). The product was characterized in THF-d8
Suzuki Coupling between 23 and 4-(4-Methylpiperazine-1-
carbonyl)phenylboronic Acid Pinacol Ester (24). 4-(6-
Chloroimidazo[1,2-a]pyrazin-3-yl)phenyl acetate (23, 30 mg, 0.104
mmol, 1.0 equiv), 4-(4-methylpiperazine-1-carbonyl)phenylboronic
acid pinacol ester (24, 51.7 mg, 0.156 mmol, 1.5 equiv), and sodium
carbonate (44.7 mg, 0.417 mmol, 4.0 equiv) were charged in a
nitrogen-flushed 0.5−2.0 mL Biotage vial with a magnetic stir bar.
The solids were dissolved in a 5:1 mixture of DME (521 μL) and
water (100 μL), and the solution was then sparged with a flow of
nitrogen for 5 min. The mixture was treated with 1,1′-bis-
(diphenylphosphino)ferrocene dichloropalladium(II) (7.63 mg, 10
mol %, 0.0104 mmol, 0.1 equiv), and the vial was capped with a
microwave cap. The reaction was then heated to 120 °C under
microwave irradiation (Biotage Initiator, 300 W, high absorption) for
1 h and 30 min. The reaction was cooled to rt and transferred to a 50
mL round bottom flask. The vial was rinsed with DCM, and silica gel
was added (2 g). The suspension was evaporated to dryness to obtain
a brown solid residue. The crude product was then purified by flash
chromatography using a 25 g SNAP Ultra column (100% EtOAc to
50% MeOH in 50% EtOAc over 25 CV) to yield the desired
compound 25. The solid was then purified again using reverse-phase
chromatography on a 12 g SNAP C18 Ultra column. A gradient of
100% 10 mM ammonium formate-buffered solution in water (AMF)
to 50% MeCN in 50% AMF over 25 CV was used. The fractions
containing pure compound were lyophilized overnight. Compound 25
was isolated as a white free-flowing solid as a formate salt (34 mg,
77%). Product 25 corresponds to literature characterization.19 1H
NMR (400 MHz, CDCl3): δ 9.21 (d, J = 1.2 Hz, 1H), 8.54 (d, J = 1.2
Hz, 1H), 8.25 (s, 1H (formate)), 7.96 (d, J = 8.4 Hz, 2H), 7.83 (s,
1H), 7.52 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.06 (d, J =
8.8 Hz, 2H), 3.93 (br s, 2H), 3.73 (br s, 2H), 2.79 (br s, 4H), 2.54 (s,
3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 168.1, 165.2
(formate), 158.2, 142.2, 139.2, 137.1, 136.9, 135.1, 133.8, 128.8,
127.2, 126.8, 125.6, 116.8, 115.8, 113.1, 53.9, 46.5, 45.0, 43.6, 40.9.
HRMS (ESI/Q-Exactive Orbitrap) m/z: [M + H]+ calcd for
C24H24N5O2, 414.1925; found, 414.1917.
1
as it is poorly soluble in CDCl3. H NMR (400 MHz, THF-d8): δ
9.36 (d, J = 6.8 Hz, 1H), 9.09 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 6.8,
8.4 Hz, 1H), 7.75−7.70 (m, 4H), 4.71 (br d, J = 1.5 Hz, 1H), 4.51 (br
d, J = 1.5 Hz, 1H). 13C{1H} NMR (126 MHz, THF-d8): δ 154.3,
1
147.8, 146.0, 143.5, 133.6, 133.1, 128.7, 127.9, 127.0 (q, J = 272.2
Hz, JC−F), 124.9, 122.1 (q, 1J = 323.8 Hz, JC−F), 71.6, 42.8. 19F NMR
(471 MHz, THF-d8): δ −74.47 (s), −75.57 (s). IR ν: 3098, 1593,
1426, 1396, 1269, 1251 cm−1. HRMS (ESI/Q-Exactive Orbitrap) m/
z: [M − OTf]+ calcd for C14H9Br2ClF3N2O2S, 520.8359; found,
520.8366.
Experimental Procedure for the Reaction between 3-
Bromo-1-(2-(4-bromophenyl)-1-((trifluoromethyl)sulfonyl)-
aziridin-2-yl)-2-chloropyridin-1-ium (19g) and Et3N (Scheme
4). 3-Bromo-1-(2-(4-bromophenyl)-1-((trifluoromethyl)sulfonyl)-
aziridin-2-yl)-2-chloropyridin-1-ium (19g) (30 mg, 0.045 mmol, 1.0
equiv) was charged in a flame-dried, nitrogen-flushed 2−5 mL Biotage
microwave tube under a nitrogen atmosphere. Anhydrous chloroform
(0.23 mL, 0.2 M) was added, and the suspension was stirred for 2
min. Triethylamine (9.1 mg, 13 μL, 0.090 mmol, 2.0 equiv) was
added in one portion. The solid gradually solubilized, and the reaction
was stirred at room temperature for 1 h. LCMS indicated full
conversion of the pyridinium salt to the desired imidazo[1,2-
a]pyridine 10g. The solvent was evaporated under vacuo, and the
crude product was then purified by flash chromatography using a 25 g
SNAP Ultra column (100% heptanes to 50% EtOAc in 50% heptanes
over 20 CV) to yield the desired compound 10g (13 mg, 77%) as a
1
red oil. H NMR spectra match the characterization data previously
ASSOCIATED CONTENT
■
reported.
sı
* Supporting Information
Synthesis of Highly Potent Mnk1/Mnk2 Inhibitor (Scheme
6). Formation of 4-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)phenyl
Acetate (23) via Optimized Conditions. The azirine (8l, 516 mg,
2.95 mmol, 1.0 equiv), sodium sulfate (516 mg), and 2,5-
dichloropyrazine (878 mg, 5.89 mmol, 2.0 equiv) were loaded in a
flame-dried, nitrogen-flushed 20 mL Biotage microwave tube under a
nitrogen atmosphere. Anhydrous chloroform (14.7 mL, 0.2 M) was
added, and the mixture was stirred until complete dissolution of the
azirine. The solution was cooled to −20 °C in a water/isopropanol
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02148.
General information and reagents, control reactions,
isolation and characterization of reaction intermediates,
1
optimization tables, and copies of H NMR, 13C{1H}
NMR, 19F NMR, and FTIR spectra (PDF)
L
https://dx.doi.org/10.1021/acs.joc.0c02148
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Garcia, M.; Martinez, J.; Masurier, N. Imidazopyridine-fused [1,3]-
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FAIR data and the primary NMR FID files for
compounds: 8a−8n, 10a−10t, 14b−14n, 18, 19g, 23,
25, and S1 (ZIP)
(3) (a) Ji, J.-J.; Zhu, Z.-Q.; Xiao, L.-J.; Guo, D.; Zhu, X.; Tang, J.;
Wu, J.; Xie, Z.-B.; Le, Z.-G. Photocatalyst-free decarboxylative
aminoalkylation of imidazo[1,2-a]pyridines with N-aryl glycines
enabled by visible light. Org. Chem. Front. 2019, 6, 3693−3697.
(b) Gunaganti, N.; Kharbanda, A.; Lakkaniga, N. R.; Zhang, L.;
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imidazo[1,2-a]pyridines to rapidly access new chemical space for drug
discovery efforts. Chem. Commun. 2018, 54, 12954−12957. , and
references cited therein
AUTHOR INFORMATION
Corresponding Author
Guillaume Pelletier − Department of Chemical Sciences,
Paraza Pharma Inc., Saint-Laurent, Québec H4S 2E1,
Canada; orcid.org/0000-0002-3485-5416;
Email: guillaume.pelletier@parazapharma.com
■
(4) For recent examples, see: (a) Reddy, R. J.; Shankar, A.; Kumari,
A. H. An Efficient Sequential One-Pot Approach for the Synthesis of
C3-Functionalized Imidazo[1,2-a]pyridines under Transition-Metal
Free Conditions. Asian J. Org. Chem. 2019, 8, 2269−2275. (b) Said,
M. S.; Mishra, A.; Pandole, S.; Nayak, R. A.; Kumar, P.; Gajbhiye, J.
M. Regioselective One-Pot Synthesis of 3-Fluoro-Imidazo[1,2-a]-
pyridines from Styrene. Asian J. Org. Chem. 2019, 8, 2143−2148.
(c) Liu, Y.; Zhang, Y.; Sun, J. Copper-Promoted Annulation of
Terminal Alkynes with 2-Aminopyridines to Assemble 2-Halogenated
Imidazo[1,2- a]pyridines. J. Heterocycl. Chem. 2019, 56, 2804−2810.
(d) Chen, Z.; Liang, P.; Xu, F.; Qiu, R.; Tan, Q.; Long, L.; Ye, M.
Lewis Acid-Catalyzed Intermolecular Annulation: Three-Component
Reaction toward Imidazo[1,2-a]pyridine Thiones. J. Org. Chem. 2019,
84, 9369−9377. (e) Penteado, F.; Gomes, C. S.; Perin, G.; Garcia, C.
Authors
́
́
Frederic Vuillermet − Department of Chemical Sciences,
Paraza Pharma Inc., Saint-Laurent, Québec H4S 2E1,
Canada
Joanick Bourret − Department of Chemical Sciences, Paraza
Pharma Inc., Saint-Laurent, Québec H4S 2E1, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02148
Author Contributions
†F.V. and J.B. contributed equally.
Notes
The authors declare no competing financial interest.
S.; Bortolatto, C. F.; Bruning, C. A.; Lenardao, E. J. Regioselective
̈ ̃
Synthesis of 1-Sulfanyl- and 1-Selanylindolizines. J. Org. Chem. 2019,
84, 7189−7198. (f) Zhou, B.; Yuan, Y.; Jin, H.; Liu, Y. I2O5-Mediated
Iodocyclization Cascade of N-(1-Arylallyl)pyridine-2-amines with
Concomitant C=C Bond Cleavage: A Synthesis of 3-Iodoimidazo-
[1,2-a]pyridines. J. Org. Chem. 2019, 84, 5773−5782. (g) Hou, Z.-W.;
Mao, Z.-Y.; Melcamu, Y. Y.; Lu, X.; Xu, H.-C. Electrochemical
Synthesis of Imidazo-Fused N-Heteroaromatic Compounds through a
C−N Bond-Forming Radical Cascade. Angew. Chem., Int. Ed. 2018,
57, 1636−1639.
ACKNOWLEDGMENTS
■
Part of the research was funded by NSERC (USRA) and
BioTalent in the form of undergraduate research awards to
F.V. and J.B. We would also like to thank Christian Perreault,
Jonathan Boudreault, and Samuel Aubert-Nicol for insightful
discussions. Robin Larouche-Gauthier, Dana K. Winter, Burcin
́
Akgun, Clint James, Alexandre Larivee, and Ramsay Beveridge
are also acknowledged for proofreading this article. The
authors are much obliged to NeoMed Institute and Paraza
Pharma Inc. We would like to acknowledge Limei Tao (Paraza
Pharma Inc.), Serge Bourg (Paraza Pharma Inc.), Alexandra
(5) (a) Reen, G. K.; Kumar, A.; Sharma, P. Recent advances on the
transition-metal-catalyzed synthesis of imidazopyridines: an updated
coverage. Beilstein J. Org. Chem. 2019, 15, 1612−1704. (b) Tian, L.-
L.; Lu, S.; Zhang, Z.-H.; Huang, E.-L.; Yan, H.-T.; Zhu, X.; Hao, X.-
Q.; Song, M.-P. Copper-Catalyzed Double Thiolation To Access
Sulfur-Bridged Imidazopyridines with Isothiocyanate. J. Org. Chem.
2019, 84, 5213−5221. (c) Kilic, H.; Turgut, M.; Yilmaz, M. S.;
́
́
Furtos and Karine Gilbert (Centre Regional de Spectrometrie
́
́
de Masse de l’Universite de Montreal) for HRMS measure-
ments along with Pascal Turcotte (NeoMed Institute) for
FTIR measurements.
̈
Dalkilic, O.; Metin, O. Monodisperse Ni@Pd Core@Shell Nano-
particles Assembled on Reduced Graphene Oxide as a Highly
Efficient and Reusable Heterogeneous Catalyst for the C-H Bond
Arylation of Imidazo[1,2-a]pyridine with Aryl Halides. ACS
Sustainable Chem. Eng. 2018, 6, 11433−11440. (d) Lei, S.; Mai, Y.;
Yan, C.; Mao, J.; Cao, H. A Carbonylation Approach Toward
Activation of Csp2-H and Csp3-H Bonds: Cu-Catalyzed Regioselective
Cross Coupling of Imidazo[1,2-a]pyridines with Methyl Hetarenes.
Org. Lett. 2016, 18, 3582−3585. (e) Gao, Y.; Lu, W.; Liu, P.; Sun, P.
Iron-Catalyzed Regioselective Alkoxycarbonylation of Imidazohetero-
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Y.; So, C. M.; Wang, L.-l.; Kwong, F. Y. Regioselective Direct C-3
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Chem. 2015, 80, 1457−1463. (h) Cao, H.; Zhan, H.; Lin, Y.; Lin, X.;
Du, Z.; Jiang, H. Direct Arylation of Imidazo[1,2-a]pyridine at C-3
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