Synthesis of 3-Aminoimidazo[1,2-a]pyridines from α-Aminopyridinyl Amides

Article abstract of DOI:10.1021/acs.joc.6b01324

3-Aminoimidazo[1,2-a]pyridines are rapidly synthesized via a facile and mild cyclodehydration-aromatization reaction starting from readily available amides. The cyclodehydration step is mediated by the activation of N-Boc-protected 2-aminopyridine-containing amides by triflic anhydride (Tf₂O) in the presence of 2-methoxypyridine (2-MeO-Py). Subsequently, the addition of K₂CO₃ in THF ensured a clean deprotection-aromatization sequence to afford the desired heterocycle. A wide variety of functional groups and substitution patterns were tolerated under the optimized procedure, and good to excellent yields were obtained for the fused bicyclic 3-aza-heterocycles. In addition, the reaction was found to be scalable to gram-scale and could be performed with unprotected acyclic amide precursors. We also found that the resulting products were valuable intermediates for both Pd- and Ru-catalyzed C-H arylation reactions, allowing for the elaboration to diversely functionalized building blocks.

Full text of DOI:10.1021/acs.joc.6b01324

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Article
Synthesis of 3-Aminoimidazo[1,2-a]pyridines
from alpha-Aminopyridynyl Amides
Sophie Régnier, William Schulz Bechara, and André B. Charette
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01324 • Publication Date (Web): 26 Jul 2016
Downloaded from http://pubs.acs.org on July 27, 2016
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Synthesis of 3-Aminoimidazo[1,2-a]pyridines from α-
Aminopyridynyl Amides
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,
∆
Sophie Régnier, William S. Bechara, and André B. Charette*
Centre in Green Chemistry and Catalysis, Department of Chemistry, Université de
Montreal, P.O. Box 6128, Station Downtown, Montreal, Quebec, Canada, H3C 3J7.
andre.charette@umontreal.ca
Y
Y
N
X
R4
N
X
R4
Boc
X, Y = C, N
18 examples
up to 99% yield
2
Tf O, 2ꢀMeOꢀPy
N
N
O
R3
K
−
CO
3
, DCM, THF
2
R1
N
R2
R3
78 to 50 °C, 1 h
N
R1 R2
ABSTRACT
ꢀAminoimidazo[1,2ꢀa]pyridines are rapidly synthesized via a facile and mild cyclodehydrationꢀ
aromatization reaction starting from readily available amides. The cyclodehydration step is mediated by
3
the activation of NꢀBocꢀprotected 2ꢀaminopyridineꢀcontaining amides by triflic anhydride (Tf O) in the
2
presence of 2ꢀmethoxypyridine (2ꢀMeOꢀPy). Subsequently, the addition of K CO in THF ensured a clean
2
3
deprotectionꢀaromatization sequence to afford the desired heterocycle. A wide variety of functional
groups and substitution patterns were tolerated under the optimized procedure, and good to excellent
yields were obtained for the fused bicyclic 3ꢀazaꢀheterocycles. In addition, the reaction is found to be
scalable to gramꢀscale and could be performed with unprotected acyclic amide precursors. We also found
that the resulting products were valuable intermediates for both Pdꢀ and Ruꢀcatalyzed C−H arylation
reactions, allowing for the elaboration to diversely functionalized building blocks.
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INTRODUCTION
1
Nitrogenꢀcontaining heterocycles are omnipresent in contemporary medicinal chemistry. They
encompass a large number of natural and commercialized synthetic products, exhibiting a remarkably
diverse array of biological activities. For instance, the bicyclic imidazo[1,2ꢀa]pyridine scaffold, a pertinent
nitrogenꢀcontaining heterocycle, is increasingly reported to be a valuable drug template and building
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block. Notably, it is present in various clinically approved drugs, such as zolpidem, alpidem, olprinone,
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and zolimidine. Moreover, imidazo[1,2ꢀa]pyridines are ideal and wellꢀknown precursors of both abnormal
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Nꢀheterocyclic carbene (NHC) ligands and organic functional material, playing a critical role in the
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properties of certain optoelectronic materials.
The Cꢀ3 position of imidazo[1,2ꢀa]pyridines is an adjustable and metabolically important
branching point for several therapeutics, whereby the judicious choice of a substituent at this position has
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been shown to determine whether a clinical candidate is poorly active or a lead molecule. Consequently,
imidazo[1,2ꢀa]pyridines substituted at Cꢀ3 with an amino group have attracted increasing interest from the
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pharmaceutical industry. They are included in the structure of potent antiꢀinflammatory (I) antiꢀcancer
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(II), and antiꢀfibrosis (III) targets (examples highlighted in blue, Figure 1). In parallel to medicinal
chemistry, recent discoveries in material sciences showcase a different flavour to the potential
applications of 3ꢀaminoimidazo[1,2ꢀa]pyridines, as they were implicated in the design of a class of
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fluorescent dyes.
N
N
N
N
N
N
Cl
N
N
2
H N
O
I
O
II
(2005, Array Biopharma Inc.)
(
2014, Rigel Pharmaceuticals)
Me
2
N
N
O
N
N
S
N
N
CN
F
III
2013, Galapagos NV)
(
Figure 1. Bioactive pharmaceutical leads bearing substituted 3ꢀaminoimidazo[1,2ꢀa]pyridines.
Given the existence of a variety of functions of 3ꢀaminoimidazo[1,2ꢀa]pyridines, there comes a
need for new and convergent synthetic methods applicable toward the elaboration of these heterocyclic
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derivatives.
Many contemporary approaches rely on the GroebkeꢀBlackburnꢀBienaymé (GBB)
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multicomponent condensation (Scheme 1a). This threeꢀcomponent reaction consists of a oneꢀpot
coupling of aldehydes, 2ꢀaminopyridines (or amidines) and isocyanides. The transformation of these
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reagents to the titled heterocycles is often catalyzed by Brønsted acids (e.g. NH Cl, AcOH, HClO4,
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15c,18
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or PTSA ) or Lewis acids (e.g. Sc(OTf) ,
BiCl3, ZnCl , or SnCl •2H O ). Recent improvements to
2 2 2
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GBB heterocyclizations have disclosed the ability to use water, ionic liquids, solventꢀfree conditions,
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8a,25
as well as microwave irradiation, which increasingly provide shorter and cleaner reactions overall.
Multicomponent condensations often constitute attractive synthetic strategies for the rapid and efficient
combinatorial generation of libraries of nitrogenꢀcontaining heterocycles. However, this advantage is not
necessarily well represented with GBB heterocyclization methods, as they suffer from various drawbacks.
For instance, they are limited to toxic, costly and/or scarcely available isocyanide partners, which
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classically exhibit short halfꢀlives at ambient temperatures. Additionally, the scope of these methods is
somewhat limited; the synthesis of trisubstituted amines at the Cꢀ3 position can be troublesome; and Cꢀ2
15ꢀ
unsubstituted 3ꢀaminoimidazo[1,2ꢀa]pyridines are rarely synthesized following typical GBB procedures.
25,27
Scheme 1. Strategies for the Synthesis of 3ꢀAminoimidazo[1,2ꢀa]pyridines
(
a) Groebke-Blackburn-Bienaymé Reaction
R1
R1
O
GBB
R2
+
+
N
NC
N
R3
Multicomponent
Condensation
N
NH
2
R2
N
H
R3
(
b) Condensation of Ketones with 2-Aminopyridines
R1
R1
O
I
2
+
N
N
Ar
DMSO
00 °C
N
NH2
1
R1
N
Ar
N
H
(
c) Annulation of α-Keto Vinyl Azides and 2-Aminopyridines
H)Ar
(
R1
O
1
) THF, reflux
+
Ar1
Ar2
N
N
2) Remove THF
N
NH2
N3
NaBH , MeOH
4
N
Ar2
Ar1
H
An alternative method for the synthesis 3ꢀaminoimidazo[1,2ꢀa]pyridines relies on the
2
8
condensation of aromatic ketones with 2 equivalents of 2ꢀaminopyridines (Scheme 1b). This strategy is
also not general, and the scope is inherently limited to preparing 2ꢀaminopyridyls with substituents at the
Cꢀ3 position and the use of acetophenone precursors. A complementary strategy for the synthesis of 3ꢀ
aminoimidazo[1,2ꢀa]pyridines is reported to proceed via sequential annulation of αꢀketo vinyl azide units
and 2ꢀaminopyridines followed by reduction of the corresponding imine, allowing for the formation of
products with monoꢀsubstituted Cꢀ3ꢀamino groups (Scheme 1c). The methodology is practical, but the
2
9
scope is limited to aryl substitutions on the αꢀketo vinyl azide partner. The development of a robust,
general synthetic method for synthesising structurally diverse imidazo[1,2ꢀa]pyridines with high levels of
chemoselectivity is a desirable, yet currently unrealized goal. Our previous work with triflic anhydride
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(
Tf O) mediated activation of amides inspired us to pursue a complementary strategy towards these
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heterocycles. We aimed to develop an operationally simple conditions that may be used to introduce a
wide variety of substitution patterns within the 3ꢀaminoimidazo[1,2ꢀa]pyridines scaffold.
Various methods based on the chemoselective electrophilic activation of amides in the presence
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of Tf O have found broad applications in the synthesis of valuable building blocks.
An example of
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such strategy can be found in our recently reported intramolecular cyclodehydrationꢀaromatization work
towards the synthesis of imidazo[1,5ꢀa]pyridines (2), a constitutional isomer, from activated secondary
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2
amides (1) (Scheme 2a). In these earlier studies, we determined that the use of 2ꢀmethoxypyridine (2ꢀ
MeOꢀPy), a slightly basic additive, is required for the activation step in order to obtain an efficient
3
3,30a
conversion to the desired target.
Inspired by these results, we envisioned developing an analogous
route that would allow the synthesis of 3ꢀaminoimidazo[1,2ꢀa]pyridines (4) from both tertiary and
secondary amides (3) (Scheme 2b).
Scheme 2. Synthesis of Imidazo[1,5ꢀa]azines and 3ꢀAminoimidazo[1,2ꢀa]pyridines by Tf OꢀMediated
2
Activation of Amides
RESULTS AND DISCUSSION
We initially investigated the synthesis of 4a by applying the previously reported activation
conditions to 3a, a simple amide bearing a tertꢀbutoxycarbonyl (Boc) protecting group accessed in two
steps from commercially available 2ꢀBocꢀaminopyridine. In the presence of 2ꢀMeOꢀPy in DCM (DCM) at
ambient temperature, the desired product 4a was obtained in 85% yield before optimization (Table 1,
entry 1). Based on our previous experience with heterocycles, such as 2, we rapidly and efficiently
optimized the overall transformation towards 4a by fineꢀtuning various parameters of the reaction.
Improved conditions for the activationꢀcyclodehydration sequence were readily obtained by employing 1.1
equiv of 2ꢀMeOꢀPy in DCM (0.6 M) while warming the reaction mixture from –78 °C to room temperature
(rt) over 30 min. to ensure complete activation of the amide. As exemplified in different methodologies
involving Tf Oꢀmediated electrophilic activation of amides, the addition of 2ꢀsubstituded pyridines as nonꢀ
2
nucleophilic and slightly basic additives in the reaction was found to be crucial to achieve an appreciable
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level of efficiency. Commonly used 2ꢀFꢀPy also works well in the activation step, although less
expensive 2ꢀMeOꢀPy was the base of choice in this methodology. Consecutively, we screened different
acidic and basic conditions for the deprotectionꢀaromatization step and found that the transformation was
very clean when performed in the presence of K CO in tetrahydrofuran (THF) at 50 °C for an additional
2
3
3
0 min. Both transformations were run in the same pot, facilitating both the workꢀup and purification
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procedures.
Table 1. Optimization of the ActivationꢀCyclodehydration Reaction Sequence
entry
base
temp.
time
(h)
1
Conc
(M)
0.2
0.6
0.6
0.6
0.6
0.6
yield 4a
a
(%)
(°C)
1
2
3
4
5
6
2ꢀMeOꢀPy
2ꢀMeOꢀPy
2ꢀMeOꢀPy
rt
85
80
86
99
90
53
rt
0.5
0.5
0 °C to rt
2ꢀMeOꢀPy –78 °C to rt 0.5
2ꢀFꢀPy
None
rt
rt
0.5
0.5
a
1
Yields determined from the crude reaction mixture by H NMR analysis using Ph CH as an internal
3
standard.
To explore the scope of the cyclodehydrationꢀaromatization sequence, various amides (3) were
evaluated under the optimized conditions (Scheme 3). All of these amides can be obtained similarly to 3a,
from commercially available NꢀBocꢀaminopyridines, bromoacetyl bromide and an equivalent of amine. To
our delight, the overall process towards the synthesis of 3ꢀaminoimidazo[1,2ꢀa]pyridines 4 was shown to
be effective in the presence of a variety of tertiary amide substrates, tolerating different substitution
patterns on both the pyridine and amide components. More precisely, cyclic and acyclic amines can be
incorporated at the Cꢀ3 position of the imidazo[1,2ꢀa]pyridines while consistently affording high yields
(
Scheme 3, 4a–4e). NꢀAryl substituted 3ꢀaminoimidazo[1,2ꢀa]pyridines 4f and 4g are also efficiently
synthesized in excellent yields. The variation of the electronic and steric properties in all positions of the
aminoimidazo[1,2ꢀa]pyridine (Cꢀ5, Cꢀ6, Cꢀ7 and Cꢀ8) is also well tolerated, as good to excellent yields
were obtained in the presence of various functional groups (compounds 4h–4n). Interestingly, product 4o,
with an alkyl substitution at Cꢀ2 position, is accessible in moderate yield under our optimized conditions.
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Notably, the described method tolerates the replacement of the pyridine ring by other heterocycles, such
as pyrimidine (4p) and pyrazine (4q). The procedure can be efficiently extended to secondary amides,
affording monoꢀsubstituted 3ꢀaminoimidazo[1,2ꢀa]pyridine 4r in excellent yield (96%). Finally, the
transformation was shown to be amenable to gramꢀscale, as product 4d was isolated with 96% yield.
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Scheme
3.
Synthesis
of
3ꢀAminoimidazo[1,2ꢀa]pyridines
from
the
Optimized
a
Cyclodehydration/Aromatization Conditions
a
b
Isolated yields. Yield obtained from 4.2 mmol of the corresponding amide precursor.
Following our success with Bocꢀprotected substrates, we decided to further expand the scope of
the current methodology by starting from an unprotected amide (Scheme 4). The treatment of amide 3s
with 2.0 equiv of Tf O instead of 1.0 equiv under the optimized conditions led to the corresponding 3ꢀ
2
aminoimidazo[1,2ꢀa]pyridine (4a) in a reasonable 51% yield following full conversion of starting amide. In
this case, the additional equivalent of Tf O is required because of initial triflation of the Nꢀ1 moiety, which
2
is ultimately cleaved in the presence of Mg(0) in MeOH at the aromatization step.
Scheme 4. Synthesis of 3ꢀAminoimidazo[1,2ꢀa]pyridine from an Unprotected Amide (3s)
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Inspired by the plethora of methodologies that exploit nitrogenꢀbased directing groups for
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transition metalꢀcatalyzed C–H arylations, we sought to take advantage of the nitrogen atom at the Nꢀ1
position of 3ꢀaminoimidazo[1,2ꢀa]pyridine 4a to perform divergent Pdꢀ and Ruꢀcatalyzed C–H
functionalization reactions. The introduction of an aryl substituent at the Cꢀ2 position was achieved by an
intermolecular Pdꢀcatalyzed direct C–H arylation reaction (Scheme 5a). Using reported conditions
developed by the Murai group with 4ꢀiodobenzotrifluoride as the coupling partner, this C–H activation
36
reaction provided the desired polysubstituted 3ꢀaminoimidazo[1,2ꢀa]pyridine 5a in 55% yield. While our
approach to 3ꢀaminoimidazo[1,2ꢀa]pyridine (Scheme 2) allows the incorporation of an alkyl group at the
Cꢀ2 position of these scaffolds (Scheme 3, compound 4o), this Pdꢀcatalyzed postꢀfunctionalization
complements the initial strategy by allowing the addition of aryl groups at the same position at later stage.
The latter approach may be advantageous for generating various Cꢀ2ꢀsubstituted heterocycles using a
combinatorial approach.
Scheme 5. Novel MetalꢀCatalyzed C−H Functionalization of 3ꢀAminoimidazo[1,2ꢀa]pyridines
(a) Pd-Catalyzed C-H Arylation of 3-aminoimidazo[1,2-a]pyridine (4a)
I
N
N
Pd(phen)2(PF6)2 (5 mol %)
Cs CO (2 equiv)
N
N
+
N
N
2
3
H
DMA, 150 °C 24 h
CF3
4a
(2 equiv)
5a
55%
CF3
(b) Ru-Catalyzed C-H Arylation of 3-aminoimidazo[1,2-a]pyridine (4m)
O
Br
[
RuCl (pꢀcymene)] (5 mol %)
2 2
MesCO2H (30 mol %)
H
N
+
N
K2CO3 (2 equiv)
PhMe (0.3 M), 130 °C, 24 h
N
N
N
O
N
4m
(3 equiv)
6a
0%
9
Considering the ability of the nitrogen atom at Nꢀ1 position to chelate palladium species, we
further pursued the polyfunctionalization of the 3ꢀaminoimidazo[1,2ꢀa]pyridine scaffold by performing a
3
7
Ruꢀcatalyzed C–H arylation at the ortho position of the phenyl group in 4m (Scheme 5b). When
imidazo[1,2ꢀa]pyridine 4m was subjected to nonꢀoptimized Ackermann C–H arylation conditions,
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employing [RuCl (pꢀcymene)] complex as the catalyst in the presence of 4ꢀbromoacetophenone, the
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monoarylated product 6a was obtained in 90% yield with the remaining 10% stemming from the diarylated
product. A distinguished feature of such ruthenium catalyzed transformation is exemplified by its siteꢀ
selectivity being complementary to traditional Pdꢀcatalyzed C–H bond arylation reactions.
Overall, we have successfully developed a mild cyclodehydrationꢀaromatization process that is
effective using short reaction times while using minimal amounts of an activating reagent. These
conditions were applied to a large panel of tertiary amides with various substitution patterns. The
methodology is also shown to be effective in the presence of an unprotected substrate (3s) or with a
secondary amide (3r). The 3ꢀaminoimidazo[1,2ꢀa]pyridine products readily engage in versatile transition
metalꢀcatalyzed C–H arylation reactions for the synthesis of more complex scaffolds. These include
intermolecular Pdꢀ and Ruꢀcatalyzed C–H functionalizations, demonstrating the efficiency of the 3ꢀ
aminoimidazo[1,2ꢀa]pyridine motif as a directing group under contemporary C–H arylation methodologies.
We expect this methodology and postꢀmodification strategies to be useful in medicinal chemistry towards
the synthesis of novel drug candidates.
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EXPERIMENTAL SECTION
General Information
Unless otherwise stated, all glassware was stored in the oven and/or was flameꢀdried prior to use. All
38
reactions were set up under an argon atmosphere while adding reagents and were run with the
exclusion of moisture. All reaction flasks were kept closed with a septum during the reaction time.
Anhydrous solvents were obtained either by filtration through drying columns (THF, DCM, toluene) or by
distillation over CaH (MeOH) or BaO (DMA). Analytical thinꢀlayer chromatography (TLC) was performed
2
on precoated, glassꢀbacked silica gel. Visualization of the developed chromatogram was performed by
UV absorbance (254nm), UV fluorescence (350nm) or aqueous potassium permanganate (KMnO ). Flash
4
column chromatography was performed on an automatic purification system. Prepacked normal phase
silica gel columns (12 g, 24 g, 40 g, 80 g and 120 g) were used for separation of products. Melting points
were obtained on a melting point apparatus and are uncorrected. Nuclear magnetic resonance spectra
1
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19
(
H NMR, C NMR and F NMR) were recorded on 400 MHz and 500 MHz spectrometers. Chemical
1
shifts for H NMR spectra are recorded in parts per million from tetramethylsilane using the central peak
of chloroform (CHCl ) (δ = 7.26 ppm), MeOH (δ = 3.31 ppm) or HDO (δ = 4.79 ppm) as the internal
3
1
3
standard. Chemical shifts for C NMR spectra are recorded in parts per million from tetramethylsilane
1
3
using the central peak of CDCl (δ = 77.23 ppm), as the internal standard. All C NMR spectra were
3
1
9
obtained with complete proton decoupling. Chemical shifts for F NMR spectra are recorded in parts per
million from trichlorofluoromethane using the central peak of trifluorotoluene (δ = ꢀ63.72 ppm) as the
internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet and br = broad), coupling constant in Hz and integration. Infrared spectra
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are reported in reciprocal centimeters (cm ). High resolution mass spectra were performed by positive
electrospray ionization on a TOF analyzer.
Reagents
Unless otherwise stated, commercial reagents were used without purification. Trifluoromethanesulfonic
anhydride (Tf O) was made by heating TfOH on P O , distilled and kept under argon in a Schlenk flask
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before use. 2ꢀMethoxypyridine was distilled over 4Å molecular sieves and kept under argon before use.
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[
Pd(phen) ][PF ] was synthesized according to previously reported procedures.
2 6 2
Experimental Procedure and Characterization Data
Synthesis of Carbamates
Procedure A: To a 50ꢀmL round bottom flask equipped with a magnetic stirrer was added 2ꢀ
aminopyridine (25 mmol; 1 equiv.) in THF (12.5 mL; 2M). Boc O (27.5 mmol; 1.1 equiv) was added in one
2
portion and the resulting mixture was stirred at rt for 16 h. Solvents were then removed under reduced
pressure and the residue was dissolved in DCM and washed with sat. NaHCO and brine. The combined
3
organic layers were dried on Na SO , filtered and concentrated under reduced pressure. The residue thus
2
4
obtained was purified by automated flash chromatography over high performance silica gel (40ꢀg column)
using a gradient of 0% to 30% EtOAc/Hexanes with a flow of 45 mL/min. The crude amide was injected
using a dry pack of silica gel. Fractions containing the carbamate were concentrated to dryness.
Procedure B: To a flame dried 50ꢀmL round bottom flask equipped with a magnetic stirrer was added
NaHMDS (4.2 mmol; 2.1 equiv) and THF (10 mL; 0.2M). The aminopyridine was added slowly at 0 °C and
the resulting mixture was stirred at this temperature for 30 minutes before the dropwise addition of Boc O
2
(
2.4 mmol; 1.2 equiv). The reaction mixture was then allowed to warm up to rt and was stirred for 16h.
Excess NaHMDS was quenched with methanol at 0°C and the solvents were removed under reduced
pressure. DCM was added and the mixture was washed with sat. NaHCO and brine. The combined
3
organic layers were dried over Na SO , filtered and concentrated under reduced pressure. The residue
2
4
thus obtained was purified by automated flash chromatography over high performance silica gel (40 g
column) using a gradient of 0% to 30% EtOAc/Hexanes with a flow of 45 mL/min. The crude amide was
injected using a dry pack of silica gel. Fractions containing the carbamate were concentrated to dryness.
Characterization Data of Carbamates
tert-Butyl (3-methoxypyridin-2-yl)carbamate: Following general procedure B. The crude
aminopyridine was purified by flash chromatography over silica gel using a gradient of 0% to 30%
EtOAc/Hexanes. The crude amide was injected using a dry pack of silica gel over a 24 g column and a
flow of 35 mL/min was used. Fractions containing A was obtained as a yellow oil (1.5 mmol; 334 mg; 37%
1
yield). Rf: 0.30 (30% Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.06 (d, J=4.8 Hz, 1 H),
3
7.37 (br. s, 1 H), 7.09 (dd, J=8.0, 1.2 Hz, 1 H), 6.93 (dd, J=8.0, 5.0 Hz, 1 H), 3.88 (s, 3 H), 1.54 (s, 9 H);
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C NMR (CDCl , 126MHz): δ 150.8, 143.7, 142.3, 139.3, 118.0, 116.6, 80.9, 55.5, 28.2; HRMS (ESI,
3
ꢀ
1
Pos): calc. for C H N O [M+H]+: 225.1234 m/z, found: 225.1224 m/z; FTIR (cm ) (neat) 3435, 2977,
11 17
2
3
2934, 1743, 1597, 1499, 1147, 1120, 1017, 727.
tert-Butyl (5-methylpyridin-2-yl)carbamate: Following general procedure A. The crude aminopyridine
was purified by flash chromatography over silica gel using a gradient of 0% to 30% EtOAc/Hexanes. The
crude amide was injected using a dry pack of silica gel over a 24 g column and a flow of 35 mL/min was
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used. Fractions containing B was obtained as a white solid (9.6 mmol; 2 g; 96% yield). Rf = 0.46 (20%
1
Ether/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.19 (br. s., 1 H), 8.07 (d, J=2.2 Hz, 1 H), 7.91 (d,
3
1
3
J=8.6 Hz, 1 H), 7.54 (dd, J=8.6, 2.2 Hz, 1 H), 2.29 (s, 3 H), 1.54 (s, 9 H); C NMR (CDCl , 126MHz): δ
3
152.4, 149.6, 146.1, 139.8, 127.6, 112.2, 81.1, 28.3, 17.6; HRMS (ESI, Pos): calcd for C H N O
11 17 2 2
ꢀ
1
[M+H]+: 209.1285 m/z, found: 209.1291 m/z; mp: 138ꢀ140 °C; FTIR (cm ) (neat): 3169, 2973, 2924,
716, 1523, 1155, 1053, 1026, 766.
1
tert-Butyl pyrazin-2-ylcarbamate: Following general procedure A. The crude aminopyridine was
purified by flash chromatography over silica gel using a gradient of 0% to 30% EtOAc/Hexanes. The
crude amide was injected using a dry pack of silica gel over a Gold 24 g column and a flow of 35 mL/min
was used. Fractions containing C was obtained as a white solid (6.7 mmol; 1.31 g; 67% yield). Rf = 0.43
1
(30% EtOAc/Petroleum Ether); H NMR (CDCl , 500MHz): δ 9.33 (s, 1 H), 8.27 (d, J=2.6 Hz, 1 H), 8.22 ꢀ
3
13
8.25 (m, 1 H), 8.20 (br. s., 1 H), 1.57 (s, 9 H); C NMR (CDCl , 126MHz): δ 151.8, 148.8, 141.6, 138.8,
3
135.9, 81.9, 28.2; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 196.1081 m/z, found: 196.1084 m/z;
9
14
3
2
ꢀ1
mp : 112ꢀ114 °C; FTIR (cm ) (neat): 3208, 2976, 1726, 1554, 1417, 1243, 1151, 1078, 1011.
Other carbamates used for the synthesis of amides 3a-r are commercially available.
General Procedures for the Synthesis of Amides 3a-r
To a 50ꢀmL round bottom flask equipped with a magnetic stirrer was added the bocꢀprotected
aminopyridine (21mmol; 1 equiv) in THF (106 mL; 0.2 M). The mixture was cooled to 0 °C and NaH (23.3
mmol; 1.1 equiv) was added. The reaction mixture was stirred at this temperature for 30 min and the
amide (21 mmol; 1 equiv) was added slowly. The mixture was then stirred at rt for another 16 h before
quenching the excess NaH with MeOH at 0 °C. Solvents were removed under reduced pressure and the
residue was dissolved in DCM. The resulting solution was washed with sat. NaHCO and brine. The
3
combined organic layers were dried over Na SO , filtered and concentrated under reduced pressure. The
2
4
residue thus obtained was purified by automated flash chromatography over high performance silica gel
24 g column) using a gradient of 0% to 30% EtOAc/Hexanes with a flow of 35 mL/min. The crude amide
(
was injected using a dry pack of silica gel. Fractions containing amide (3) were concentrated to dryness.
Characterization Data of Amides 3a-r
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tert-Butyl (2-oxo-2-(piperidin-1-yl)ethyl)(pyridin-2-yl)carbamate (3a): Following general procedure,
1
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a was obtained as a white solid (12.2 mmol; 3.9 g; 62% yield). Rf = 0.27 (30% EtOAc/Hexanes); H
NMR (CDCl , 500MHz): δ 8.28 (ddd, J=4.9, 2.0, 0.8 Hz, 1 H), 7.82 (br. s., 1 H), 7.55 ꢀ 7.70 (m, 1 H), 6.96
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(
ddd, J=7.3, 4.9, 1.0 Hz, 1 H), 4.82 (s, 2 H), 3.30 ꢀ 3.68 (m, 4 H), 1.42 ꢀ 1.75 (m, 15 H); C NMR (CDCl3,
126MHz): δ 166.7, 154.3, 154.0, 147.0, 136.9, 119.2, 81.4, 47.6, 45.7, 43.1, 28.2, 26.3, 25.5, 24.5; HRMS
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ꢀ
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(
(
ESI, Pos): calcd for C H N O [M+H]+: 320.1969 m/z, found: 320.1984 m/z; mp : 84ꢀ86 °C; FTIR (cm )
17 25 3 3
neat): 2973, 2929, 2855, 1712, 1659, 1385, 1240, 1153, 786.
tert-Butyl (2-(diethylamino)-2-oxoethyl)(pyridin-2-yl)carbamate (3b): Following general procedure,
3
b was obtained as an offꢀwhite solid (7.2 mmol; 2.2 g; 46% yield). Rf = 0.56 (30% Acetone/Petroleum
1
Ether); H NMR (CDCl , 500MHz): δ 8.28 (ddd, J=4.9, 2.0, 0.8 Hz, 1 H), 7.86 (br. s., 1 H), 7.56 ꢀ 7.71 (m,
3
1 H), 6.97 (ddd, J=7.3, 4.9, 1.0 Hz, 1 H), 4.82 (s, 2 H), 3.37 (dd, J=14.6, 7.2 Hz, 4 H), 1.51 (s, 9 H), 1.01 ꢀ
13
1
.35 (m, 6 H); C NMR (CDCl , 126MHz): δ 167.6, 154.4, 154.0, 147.0, 137.0, 119.2, 81.5, 47.5, 41.3,
3
40.6, 28.2, 14.3, 13.1; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 308.1969 m/z, found: 308.1981
1
6
25
3
3
ꢀ1
m/z; mp : 68ꢀ70 °C; FTIR (cm ) (neat): 2971, 2931, 1715, 1645, 1470, 1363, 1226, 1144, 781.
tert-Butyl (2-oxo-2-(pyrrolidin-1-yl)ethyl)(pyridin-2-yl)carbamate (3c): Following general procedure,
3
1
c was obtained as a pink oil (1.62 mmol; 495 mg; 65% yield). Rf = 0.39 (30% Acetone/Petroleum Ether);
H NMR (CDCl , 500MHz): δ 8.31 (ddd, J=5.0, 1.9, 0.8 Hz, 1 H), 7.84 (br. s., 1 H), 7.68 (t, J=7.1 Hz, 1 H),
3
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.92 ꢀ 7.10 (m, 1 H), 4.79 (s, 2 H), 3.49 (dt, J=10.0, 6.9 Hz, 4 H), 1.75 ꢀ 2.09 (m, 4 H), 1.51 (s, 9 H);
C
NMR (CDCl , 126MHz): δ 166.5, 153.7, 153.3, 146.5, 136.4, 118.6, 80.8, 47.7, 45.2, 44.9, 27.6, 25.6,
3
ꢀ1
2
3.4; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 306.1812 m/z, found: 306.1823 m/z; FTIR (cm )
1
6
24
3
3
(neat): 2973, 2874, 1708, 1656, 1435, 1366, 1226, 1148, 1061.
tert-Butyl (2-(diallylamino)-2-oxoethyl)(pyridin-2-yl)carbamate (3d): Following general procedure, 3d
1
was obtained as a colorless oil (1.34 mmol; 445 mg; 67% yield). Rf = 0.28 (30% EtOAc/Hexanes); H
NMR (CDCl , 500MHz): δ 8.21 ꢀ 8.33 (m, 1 H), 7.83 (br. s., 1 H), 7.54 ꢀ 7.66 (m, 1 H), 6.94 (ddd, J=7.2,
3
4
.9, 0.9 Hz, 1 H), 5.63 ꢀ 5.94 (m, 2 H), 5.05 ꢀ 5.35 (m, 4 H), 4.82 (s, 2 H), 3.85 ꢀ 4.08 (m, 4 H), 1.50 (s, 9
13
H); C NMR (CDCl , 126MHz): δ 168.5, 154.2, 153.9, 146.9, 136.9, 133.1, 132.5, 119.2, 119.1, 117.3,
3
1
16.9, 81.5, 48.5, 48.3, 47.4, 28.1; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 332.1969 m/z, found:
18 26 3 3
ꢀ
1
3
32.1971 m/z; FTIR (cm ) (neat): 2978, 1712, 1664, 1590, 1469, 1367, 1223, 1151, 730.
tert-Butyl 4-(N-(tert-butoxycarbonyl)-N-(pyridin-2-yl)glycyl)piperazine-1-carboxylate (3e): Following
general procedure, 3e was obtained as a white solid (2.16 mmol; 911 mg; 89% yield). Rf = 0.25 (10%
1
Acetone/Petroleum ether); H NMR (CDCl , 500MHz): δ 8.22 ꢀ 8.34 (m, 1 H), 7.82 (br. s., 1 H), 7.64 (td,
3
J=7.8, 1.9 Hz, 1 H), 6.99 (dd, J=6.8, 5.3 Hz, 1 H), 4.85 (s, 2 H), 3.35 ꢀ 3.67 (m, 8 H), 1.50 (d, J=16.5 Hz,
13
1
8 H); C NMR (CDCl , 126MHz): δ 167.2, 154.3, 153.9, 153.6, 146.9, 136.9, 119.0, 119.0, 81.5, 80.1,
3
47.3, 44.4, 41.6, 28.2, 28.0; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 421.2446 m/z, found:
2
1
32
4
5
ꢀ
1
4
21.2448 m/z; mp : 124ꢀ126 °C; FTIR (cm ) (neat): 2973, 2931, 1682, 1413, 1365, 1235, 1151, 1019,
779.
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tert-Butyl (2-(diphenylamino)-2-oxoethyl)(pyridin-2-yl)carbamate (3f): Following general procedure,
1
3
f was obtained as a white solid (1.02 mmol; 410 mg; 51% yield). Rf = 0.29 (30% EtOAc/Hexanes); H
NMR (CDCl , 500MHz): δ 8.34 (dd, J=4.9, 1.0 Hz, 1 H), 7.84 (br. s., 1 H), 7.57 ꢀ 7.68 (m, 1 H), 7.31 (br. s,
3
13
1
0 H), 6.98 (ddd, J=7.2, 4.9, 0.7 Hz, 1 H), 4.65 (s, 2 H), 1.56 (s, 9 H); C NMR (CDCl , 126MHz): δ
3
168.6, 154.0, 153.8, 147.0, 141.9, 136.9, 129.4, 128.8, 125.7, 119.1, 119.0, 81.6, 49.5, 28.2; HRMS (ESI,
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8
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7
8
9
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7
8
9
0
ꢀ
1
Pos): calcd for C H N O [M+H]+: 404.1969 m/z, found: 404.1987 m/z; mp : 46ꢀ52 °C; FTIR (cm )
2
4
26
3
3
(
neat): 2974, 1687, 1589, 1469, 1366, 1227, 1147, 755, 692.
tert-Butyl (2-(ethyl(phenyl)amino)-2-oxoethyl)(pyridin-2-yl)carbamate (3g): Following general
procedure, 3g was obtained as an offꢀwhite solid (2.25 mmol; 800 mg, 99% yield). Rf = 0.40 (30%
1
EtOAc/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.30 (d, J=3.5 Hz, 1 H), 7.80 (br. s., 1 H), 7.57 ꢀ
3
7.67 (m, 1 H), 7.42 ꢀ 7.51 (m, 2 H), 7.34 ꢀ 7.41 (m, 1 H), 7.29 (d, J=7.3 Hz, 2 H), 6.93 ꢀ 7.01 (m, 1 H), 4.44
13
(
s, 2 H), 3.77 (q, J=7.2 Hz, 2 H), 1.53 (s, 9 H), 1.13 (t, J=7.2 Hz, 3 H); C NMR (CDCl , 126MHz): δ
3
168.0, 154.2, 153.8, 146.9, 141.2, 137.1, 129.8, 128.5, 128.2, 119.4, 119.2, 81.5, 48.9, 44.2, 28.2, 13.1;
HRMS (ESI, Pos): calcd for C H N O [M+H]+: 356.1969 m/z, found: 356.1976 m/z; mp : 118ꢀ120 °C;
2
0
26
3
3
ꢀ
1
FTIR (cm ) (neat): 3058, 2971, 2930, 1713, 1666, 1376, 1149, 786, 697.
tert-Butyl (6-methylpyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3h): Following general
procedure, 3h was obtained as a white solid (3.6 mmol; 1.2 g; 75% yield). Rf = 0.30 (30%
1
EtOAc/Petroleum Ether); H NMR (CDCl , 500MHz): δ 7.59 (br. s., 1 H), 7.47 ꢀ 7.55 (m, 1 H), 6.83 (d,
3
1
3
J=7.3 Hz, 1 H), 4.81 (s, 2 H), 3.24 ꢀ 3.74 (m, 4 H), 2.44 (s, 3 H), 1.39 ꢀ 1.8 (m, 15 H); C NMR (CDCl3,
26MHz): δ 166.9, 155.9, 154.1, 153.6, 137.4, 118.7, 116.8, 81.3, 47.7, 45.8, 43.1, 30.9, 28.2, 26.3, 25.5,
24.6, 24.1; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 334.2125 m/z, found: 334.2135 m/z; mp : 78
1
1
8
28
3
3
ꢀ1
ꢀ
80 °C; FTIR (cm ) (neat): 2974, 2933, 2856, 1710, 1657, 1455, 1364, 1223, 1152.
tert-Butyl (6-bromopyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3i): Following general
procedure, 3i was obtained as an offꢀwhite solid (0.74 mmol; 294 mg; 74% yield). Rf = 0.28 (30%
1
EtOAc/Petroleum Ether); H NMR (CDCl , 500MHz): δ 7.86 (br. s., 1 H), 7.46 (dd, J=8.3, 7.7 Hz, 1 H),
3
13
7
.12 (dd, J=7.5, 0.6 Hz, 1 H), 4.78 (s, 2 H), 3.30 ꢀ 3.73 (m, 4 H), 1.38 ꢀ 1.91 (m, 15 H); C NMR (CDCl3,
126MHz): δ 166.3, 154.2, 153.5, 139.2, 138.2, 122.7, 117.3, 82.1, 47.3, 46.0, 43.3, 28.1, 26.2, 25.5, 24.6;
HRMS (ESI, Pos): calcd for C H BrN O [M+H]+: 398.1074 m/z, found: 398.1090 m/z; mp : 96 ꢀ 100 °C;
1
7
25
3
3
ꢀ
1
FTIR (cm ) (neat): 2974, 2934, 2856, 1654, 1437, 1364, 1229, 1149, 1127.
tert-Butyl (5-methylpyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3j): Following general
procedure, 3j was obtained as an offꢀwhite solid (1.43 mmol; 477 mg, 72% yield). Rf = 0.47 (30%
1
Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.08 (dd, J=1.7, 0.7 Hz, 1 H), 7.66 (br. s., 1 H),
3
1
3
7
.35 ꢀ 7.50 (m, 1 H), 4.77 (s, 2 H), 3.23 ꢀ 3.68 (m, 4 H), 2.24 (s, 3 H), 1.39 ꢀ 1.77 (m, 15 H); C NMR
(CDCl , 126MHz): δ 166.7, 154.0, 152.1, 146.9, 137.7, 128.6, 119.3, 81.1, 47.7, 45.6, 43.0, 28.1, 26.2,
3
2
5.4, 24.4, 17.6; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 334.2125 m/z, found: 334.2112 m/z;
18 28 3 3
ꢀ
1
mp : 82ꢀ84 °C; FTIR (cm ) (neat): 2975, 2921, 2857, 1702, 1651, 1482, 1384, 1229, 1154.
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tert-Butyl (5-bromopyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3k): Following general
procedure, 3k was obtained as an offꢀwhite solid (0.50 mmol; 200 mg, 50% yield). Rf = 0.43 (30%
1
EtOAc/Hexanes); H NMR (CDCl , 500MHz): δ 8.23 ꢀ 8.40 (m, 1 H), 7.80 (br. s., 1 H), 7.72 (m, 2.5 Hz, 1
3
13
H), 4.81 (s, 2 H), 3.27 ꢀ 3.71 (m, 4 H), 1.43 ꢀ 1.80 (m, 15 H); C NMR (CDCl , 126MHz): δ 166.4, 153.6,
3
153.0, 147.6, 139.6, 82.0, 47.5, 45.8, 43.2, 28.2, 26.3, 25.5, 24.5; HRMS (ESI, Pos): calcd for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
1
C H BrN O [M+H]+: 398.1074 m/z, found: 398.1077 m/z; mp : 104ꢀ108 °C; FTIR (cm ) (neat): 2934,
1
7
25
3
3
2855, 1702, 1652, 1464, 1365, 1223, 1152, 836.
tert-Butyl (4-chloropyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3l): Following general
procedure, 3l was obtained as a yellow oil (0.70 mmol; 248 mg, 64% yield). Rf = 0.28 (30%
1
EtOAc/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.16 (d, J=5.3 Hz, 1 H), 7.99 (br. s., 1 H), 6.96 (dd,
3
13
J=5.5, 1.8 Hz, 1 H), 4.84 (s, 2 H), 3.33 ꢀ 3.68 (m, 4 H), 1.46 ꢀ 1.83 (m, 15 H); C NMR (CDCl , 126MHz):
3
δ 166.4, 155.2, 153.6, 147.5, 144.5, 119.4, 118.8, 82.1, 47.3, 45.8, 43.2, 28.1, 26.3, 25.5, 24.5; HRMS
ꢀ
1
(ESI, Pos): calcd for C H ClN O [M+H]+: 354.1579 m/z, found: 354.1593 m/z; FTIR (cm ) (neat): 2975,
1
7
25
3
3
2936, 2851, 1703, 1645, 1384, 1233, 1149, 843.
tert-Butyl (2-oxo-2-(piperidin-1-yl)ethyl)(3-phenylpyridin-2-yl)carbamate (3m): Following general
procedure, 3m was obtained as a colorless oil (0.71 mmol; 281 mg, 99% yield). Rf = 0.51 (10%
1
MeOH/DCM); H NMR (CDCl , 500MHz): δ 8.35 (dd, J=4.7, 1.6 Hz, 1 H), 7.63 ꢀ 7.94 (m, 3 H), 7.43 (t,
3
J=7.6 Hz, 2 H), 7.32 (d, J=7.0 Hz, 1 H), 7.19 (dd, J=7.5, 4.8 Hz, 1 H), 4.59 ꢀ 5.11 (m, 2 H), 3.38 ꢀ 3.74 (m,
13
4 H), 1.52 ꢀ 1.71 (m, 6 H), 0.99 (br. s., 9 H); C NMR (CDCl , 126MHz): δ 166.7, 153.8, 152.1, 146.5,
3
1
39.3, 139.2, 133.6, 128.6, 128.4, 127.4, 121.5, 81.1, 49.4, 46.1, 43.1, 27.4, 26.3, 25.5, 24.6; HRMS
ꢀ
1
(ESI, Pos): calcd for C H N O [M+H]+: 396.2287 m/z, found: 396.2283 m/z; FTIR (cm ) (neat):
2
3
30
3
3
3059,2978, 2934, 2856, 1657, 1365, 1236, 1153, 701.
tert-Butyl (3-methoxypyridin-2-yl)(2-oxo-2-(piperidin-1-yl)ethyl)carbamate (3n): Following general
procedure, 3n was obtained as a brown oil (1.06 mmol; 371 mg, 72% yield). Rf = 0.30 (30%
1
Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 7.92 (dd, J=4.8, 1.5 Hz, 1 H), 7.16 (dd, J=8.2,
3
1
.4 Hz, 1 H), 7.07 (dd, J=8.3, 4.8 Hz, 1 H), 4.64 (s, 2 H), 3.87 (s, 3 H), 3.31 ꢀ 3.55 (m, 4 H), 1.43 ꢀ 1.68
13
(
m, 6 H), 1.37 (s, 9 H); C NMR (CDCl , 126MHz): δ 166.4, 153.8, 150.6, 145.0, 138.7, 122.1, 118.8,
3
8
3
7
0.4, 55.4, 53.3, 49.1, 45.7, 42.9, 27.9, 26.1, 25.3, 24.4; HRMS (ESI, Pos): calcd for C H N O [M+H]+:
18 28 3 4
ꢀ
1
50.2074 m/z, found: 350.2080 m/z; FTIR (cm ) (neat): 2977, 2935, 2856, 1699, 1659, 1451, 1365, 1157,
27.
tert-Butyl (1-oxo-1-(piperidin-1-yl)butan-2-yl)(pyridin-2-yl)carbamate (3o): Following general
procedure, 3o was obtained as a colorless oil (0.36 mmol; 126 mg, 36% yield). Rf = 0.63 (30%
1
Acetone/Petroleum ether); H NMR (CDCl , 500MHz): δ 8.34 ꢀ 8.45 (m, 1 H), 7.59 ꢀ 7.69 (m, 1 H), 7.40 (d,
3
J=8.3 Hz, 1 H), 7.08 (ddd, J=7.3, 4.8, 0.9 Hz, 1 H), 5.16 (t, J=7.2 Hz, 1 H), 3.34 ꢀ 3.68 (m, 4 H), 1.70 ꢀ
13
2
.06 (m, 2 H), 1.45 ꢀ 1.67 (m, 6 H), 1.41 (s, 9 H), 0.92 (t, J=7.4 Hz, 3 H); C NMR (CDCl , 126MHz): δ
3
168.8, 154.1, 153.0, 147.9, 137.1, 122.2, 121.1, 81.2, 58.0, 46.2, 43.4, 28.1, 26.2, 25.5, 24.6, 24.0, 11.0;
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2
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4
4
4
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5
5
5
5
5
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ꢀ1
HRMS (ESI, Pos): calcd for C H N O [M+H]+: 348.2282 m/z, found: 348.2296 m/z; FTIR (cm ) (neat):
1
9
30
3
3
2974, 2934, 2855, 1698, 1649, 1367, 1243, 1153, 730.
tert-Butyl (2-oxo-2-(piperidin-1-yl)ethyl)(pyrimidin-2-yl)carbamate
(3p):
Following
general
procedure, 3p was obtained as an offꢀwhite solid (1.42 mmol; 456 mg, 79% yield). Rf = 0.36 (50%
1
Acetone/Hexanes); H NMR (CDCl , 500MHz): δ 8.57 (d, J=4.8 Hz, 2 H), 6.91 (t, J=4.8 Hz, 1 H), 4.75 (s,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2
1
3
1
H), 3.28 ꢀ 3.76 (m, 4 H), 1.40 ꢀ 1.83 (m, 15 H); C NMR (CDCl , 126MHz): δ 166.2, 160.4, 157.4, 153.0,
3
15.8, 81.7, 48.4, 45.7, 43.1, 28.0, 26.2, 25.5, 24.4; HRMS (ESI, Pos): calcd for C H N O [M+H]+:
1
6
25
4
3
ꢀ
1
21.1921 m/z, found: 321.1935 m/z; mp : 134ꢀ136 °C; FTIR (cm ) (neat): 2978, 2963, 2936, 2861, 1731,
657, 1413, 1152, 794.
tert-Butyl (2-oxo-2-(piperidin-1-yl)ethyl)(pyrazin-2-yl)carbamate (3q): Following general procedure,
3q was obtained as a white solid (1.97 mmol; 631 mg, 98% yield). Rf = 0.28 (30% Acetone/Petroleum
1
Ether); H NMR (CDCl , 500MHz): δ 9.19 (br. s., 1 H), 8.02 ꢀ 8.40 (m, 2 H), 4.77 (s, 2 H), 3.20 ꢀ 3.76 (m, 4
3
13
H), 1.44 ꢀ 1.82 (m, 15 H); C NMR (CDCl , 126MHz): δ 166.0, 153.2, 151.1, 141.2, 140.9, 138.2, 82.6,
3
4
6.9, 45.8, 43.2, 28.1, 26.3, 25.5, 24.5; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 321.1921 m/z,
16 25 4 3
ꢀ
1
found: 321.1913 m/z; mp : 98 ꢀ 100 °C; FTIR (cm ) (neat): 2974, 2933, 2859, 1714, 1650, 1408, 1238,
154, 1006.
tert-Butyl
1
(2-(cyclohexylamino)-2-oxoethyl)(pyridin-2-yl)carbamate
(3r): Following general
procedure, 3r was obtained as a white solid (4.05 mmol; 1.35 g, 79% yield). Rf = 0.56 (30%
1
Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.32 ꢀ 8.40 (m, 1 H), 7.68 ꢀ 7.74 (m, 1 H), 7.61 ꢀ
3
7
.67 (m, 1 H), 7.10 (ddd, J=7.2, 5.0, 1.1 Hz, 1 H), 6.93 (d, J=6.6 Hz, 1 H), 4.37 (s, 2 H), 3.74 ꢀ 3.94 (m, 1
13
H), 1.55 ꢀ 1.95 (m, 5 H), 1.51 (s, 9 H), 1.07 ꢀ 1.44 (m, 5 H); C NMR (CDCl , 126MHz): δ 169.1, 154.4,
3
1
53.8, 147.6, 137.6, 120.5, 119.8, 82.3, 52.2, 47.8, 32.9, 28.1, 25.5, 24.5; HRMS (ESI, Pos): calcd for
ꢀ
1
C H N O [M+H]+: 334.2125 m/z, found: 334.2130 m/z; mp : 102ꢀ104 °C; FTIR (cm ) (neat): 3296,
18 28
3
3
2976, 2930, 2854, 1713, 1655, 1366, 1224, 1149.
General Procedure for the Synthesis of 3-Aminoimidazo[1,2-a]pyridines 4a-r
To a flameꢀdried and argonꢀflushed 10ꢀmL glass microwave vial equipped with a magnetic stirrer and a
rubber septum was added the amide (0.3 mmol, 1.0 equiv) in anhydrous DCM (0.5 mL, 0.60 M). 2ꢀ
methoxypyridine (2ꢀMeOPyr) (35 ꢁL, 0.33 mmol, 1.1 equiv) was added via syringe and the reaction
mixture was cooled to –78 °C. Triflic anhydride (55 ꢁL, 0.33 mmol, 1.1 equiv) was added dropwise via
syringe and the reaction mixture was stirred at –78 °C for 10 min and at rt for another 20 min. The
reaction was quenched by the addition of K CO (3.0 mmol, 10.0 equiv) and THF (2.0 mL, 0.15 M) and
2
3
then stirred at 50°C for 30 min. The residue thus obtained was purified by automated flash
chromatography over high performance silica gel (24 g column) using a gradient of 0% to 50%
Acetone/Hexanes with a flow of 35 mL/min. The crude amide was injected using a dry pack of silica gel.
Fractions containing 3ꢀaminoimidazo[1,2ꢀa]pyridines (3) were concentrated to dryness.
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Characterization Data of 3-Aminoimidazo[1,2-a]pyridines
3-(Piperidin-1-yl)imidazo[1,2-a]pyridine (4a): Following general procedure, 4a was obtained as a pale
1
brown solid (0.25 mmol; 50 mg, 99% yield). Rf = 0.31 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
7.96 (dt, J=6.8, 1.2 Hz, 1 H), 7.55 (dt, J=9.0, 1.0 Hz, 1 H), 7.24 (s, 1 H), 7.12 (ddd, J=9.1, 6.6, 1.3 Hz, 1
13
H), 6.79 (td, J=6.7, 1.0 Hz, 1 H), 2.87 ꢀ 3.06 (m, 4 H), 1.57 ꢀ 1.91 (m, 6 H); C NMR (CDCl , 126MHz): δ
3
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23
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27
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33
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35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
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57
58
59
60
1
41.6, 136.4, 123.4, 122.4, 120.5, 117.8, 111.6, 53.0, 26.1, 24.1; HRMS (ESI, Pos): calcd for C H N
12 16 3
ꢀ
1
[
M+H]+: 202.1339 m/z, found: 202.1330 m/z; mp : 68ꢀ70 °C; FTIR (cm ) (neat): 3035, 2945, 2913, 2793,
503, 1304, 1250, 750, 739.
1
N,N-Diethylimidazo[1,2-a]pyridin-3-amine (4b): Following general procedure, 4b was obtained as a
1
brown oil (47 mg, 83% yield). Rf = 0.33 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ 8.10 (d, J=7.0
3
Hz, 1 H), 7.57 (d, J=9.0 Hz, 1 H), 7.35 (s, 1 H), 7.15 (ddd, J=9.1, 6.6, 1.3 Hz, 1 H), 6.81 (td, J=6.7, 1.0 Hz,
13
1
H), 3.08 (q, J=7.2 Hz, 4 H), 1.03 (t, J=7.1 Hz, 6 H); C NMR (CDCl , 126MHz): δ 141.7, 133.1, 124.1,
3
123.9, 122.7, 117.5, 111.8, 48.5, 12.6; HRMS (ESI, Pos): calcd for C H N [M+H]+: 190.1339 m/z,
1
1
16
3
ꢀ1
found: 190.1330 m/z; FTIR (cm ) (neat): 2969, 2932, 2870, 1545, 1304, 1251, 1134, 1077, 739.
3-(Pyrrolidin-1-yl)imidazo[1,2-a]pyridine (4c): Following general procedure, [1,2ꢀ a]pyridine g column
and a flow of 35 mL/min was used. Fractions containing 4c was obtained as a brown oil (0.43 mmol; 81
1
mg, 94% yield). Rf = 0.28 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ 8.00 (d, J=7.0 Hz, 1 H), 7.57
3
(
d, J=9.0 Hz, 1 H), 7.23 (s, 1 H), 7.12 (ddd, J=9.0, 6.6, 1.2 Hz, 1 H), 6.80 (td, J=6.7, 0.8 Hz, 1 H), 3.15 ꢀ
13
3.27 (m, 4 H), 2.0 (dt, J=6.9, 3.2 Hz, 4 H); C NMR (CDCl , 126MHz): δ 141.2, 134.8, 123.6, 122.9,
3
118.4, 117.4, 111.8, 52.1, 24.5; HRMS (ESI, Pos): calcd for C H N [M+H]+: 188.1182 m/z, found:
11 14 3
ꢀ
1
188.1185 m/z; FTIR (cm ) (neat): 2963, 2927, 2873, 2826, 1548, 1299, 1132, 745, 733.
N,N-Diallylimidazo[1,2-a]pyridin-3-amine (4d): Following general procedure, 4d was obtained as a
1
colorless oil (4.06 mmol; 867 mg, 96% yield). Rf = 0.36 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
8
1
1
.08 (dd, J=6.8, 1.1 Hz, 1 H), 7.59 (d, J=9.2 Hz, 1 H), 7.33 (s, 1 H), 7.10 ꢀ 7.22 (m, 1 H), 6.83 (t, J=6.8 Hz,
1
3
H), 5.85 (ddt, J=17.0, 10.3, 6.3 Hz, 2 H), 5.09 ꢀ 5.31 (m, 4 H), 3.64 (d, J=6.2 Hz, 4 H); C NMR (CDCl3,
26MHz): δ 141.8, 134.0, 133.1, 124.8, 123.2, 122.4, 118.2, 117.8, 111.5, 56.2; HRMS (ESI, Pos): calcd
ꢀ
1
for C H N [M+H]+: 214.1339 m/z, found: 214.1339 m/z; FTIR (cm ) (neat): 3080, 2979, 2924, 2849,
13 16
3
1261, 1150, 1030, 753, 636.
tert-Butyl 4-(imidazo[1,2-a]pyridin-3-yl)piperazine-1-carboxylate (4e): Following general procedure,
1
4e was obtained as a yellow oil (0.27 mmol; 82 mg, 82% yield). Rf = 0.38 (20% MeOH/DCM); H NMR
(
CDCl , 500MHz): δ 7.99 (dt, J=6.9, 1.1 Hz, 1 H), 7.50 ꢀ 7.60 (m, 1 H), 7.29 (s, 1 H), 7.14 (ddd, J=9.1, 6.6,
3
13
1.3 Hz, 1 H), 6.81 (td, J=6.8, 0.9 Hz, 1 H), 3.57 ꢀ 3.71 (m, 4 H), 2.93 ꢀ 3.07 (m, 4 H), 1.50 (s, 9 H);
C
NMR (CDCl , 126MHz): δ 154.6, 142.2, 134.8, 123.5, 122.1, 121.7, 118.1, 111.8, 80.0, 51.7, 44.0, 28.4;
3
ꢀ
1
HRMS (ESI, Pos): calcd for C H N O [M+H]+: 303.1816 m/z, found: 303.1824 m/z; FTIR (cm ) (neat):
1
6
22
4
2
2975, 2928, 2829, 1688, 1418, 1244, 1165, 1125, 729.
N,N-Diphenylimidazo[1,2-a]pyridin-3-amine (4f): Following general procedure, 4f was obtained as a
1
brown solid (0.38 mmol; 108 mg, 99% yield). Rf = 0.42 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
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.77 ꢀ 7.89 (m, 1 H), 7.72 (d, J=9.2 Hz, 1 H), 7.58 (s, 1 H), 7.20 ꢀ 7.35 (m, 5 H), 6.99 ꢀ 7.14 (m, 5 H), 6.79
13
(
td, J=6.8, 0.9 Hz, 1 H); C NMR (CDCl , 126MHz): δ 145.5, 142.8, 129.5, 129.1, 127.6, 124.8, 123.1,
3
122.4, 120.8, 118.1, 112.7; HRMS (ESI, Pos): calcd for C H N [M+H]+: 286.1339 m/z, found: 286.1326
19 16 3
ꢀ
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m/z; mp : 136ꢀ140 °C; FTIR (cm ) (neat): 3059, 3033, 1585, 1548, 1481, 1288, 1137, 752, 690.
N-Ethyl-N-phenylimidazo[1,2-a]pyridin-3-amine (4g): Following general procedure, 4g was obtained
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
as a yellow oil (0.74 mmol; 175 mg, 99% yield). Rf = 0.2 (50% Acetone/Petroleum Ether); H NMR
(
CDCl , 500MHz): δ 7.73 (dt, J=6.8, 1.2 Hz, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.55 (s, 1 H), 7.16 ꢀ 7.24 (m, 3
3
H), 6.82 (tt, J=7.3, 1.0 Hz, 1 H), 6.77 (td, J=6.7, 0.9 Hz, 1 H), 6.52 ꢀ 6.62 (m, 2 H), 3.77 (q, J=7.2 Hz, 2 H),
13
1.29 (t, J=7.2 Hz, 3 H); C NMR (CDCl , 126MHz): δ 146.5, 143.1, 129.4, 129.2, 127.4, 124.4, 122.5,
3
118.8, 118.2, 113.3, 112.1, 46.1, 13.3; HRMS (ESI, Pos): calcd for C H N [M+H]+: 238.1339 m/z,
1
5
15
3
ꢀ
1
found: 238.1340 m/z; FTIR (cm ) (neat): 2972, 2932, 1596, 1494, 1344, 1254, 1138, 738, 692.
5-Methyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4h): Following general procedure, 4h was obtained
1
as a brown oil (0.32 mmol; 68 mg, 93% yield). Rf = 0.29 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
7.31 ꢀ 7.41 (m, 2 H), 6.96 (dd, J=9.0, 6.6 Hz, 1 H), 6.40 (d, J=6.8 Hz, 1 H), 3.18 (dt, J=11.2, 3.5 Hz, 2 H),
13
2.89 (s, 3 H), 2.70 ꢀ 2.81 (m, 2 H), 1.59 ꢀ 1.92 (m, 5 H), 1.27 ꢀ 1.45 (m, 1 H); C NMR (CDCl , 126MHz):
3
δ 143.3, 139.1, 136.4, 124.3, 123.5, 115.9, 112.9, 56.1, 25.6, 23.9, 19.3; HRMS (ESI, Pos): calcd for
ꢀ
1
C H N [M+H]+: 216.1495 m/z, found: 216.1502 m/z; FTIR (cm ) (neat): 2931, 2850, 2805, 1507, 1290,
1
3
18
3
1251, 1143, 774, 732.
5-Bromo-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4i): Following general procedure, 4i was obtained
1
as a brown oil (0.42 mmol; 119 mg, 99% yield). Rf = 0.47 (10% MeOH/DCM); H NMR (CDCl , 500MHz):
3
δ 7.49 (dd, J=8.7, 1.4 Hz, 1 H), 7.37 (s, 1 H), 6.79 ꢀ 7.03 (m, 2 H), 3.14 ꢀ 3.39 (m, 2 H), 2.73 (td, J=11.5,
13
2
1
2
7
6
.7 Hz, 2 H), 1.58 ꢀ 1.94 (m, 5 H), 1.28 ꢀ 1.49 ppm (m, 1 H); C NMR (CDCl , 126MHz): δ 144.0, 139.3,
3
24.5, 123.5, 118.5, 117.2, 112.4, 55.5, 25.3, 23.9; HRMS (ESI, Pos): calcd for C H BrN [M+H]+:
12 15
3
ꢀ1
80.0444 m/z, found: 280.0433 m/z; FTIR (cm ) (neat): 2932, 2849, 2803, 1543, 1477, 1275, 1250, 1148,
70.
-Methyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4j): Following general procedure, 4j was obtained
1
as a brown oil (0.22 mmol; 47 mg, 87% yield). Rf = 0.24 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
7
2
1
2
6
.72 (s, 1 H), 7.46 (d, J=9.4 Hz, 1 H), 7.20 (s, 1 H), 6.97 (dd, J=9.2, 1.7 Hz, 1 H), 2.90 ꢀ 3.07 (m, 4 H),
13
.35 (s, 3 H), 1.57 ꢀ 1.8 (m, 6 H); C NMR (CDCl , 126MHz): δ 139.5, 136.2, 128.7, 122.6, 120.2, 117.7,
3
16.1, 53.0, 26.0, 24.0, 18.4; HRMS (ESI, Pos): calcd for C H N [M+H]+: 216.1495 m/z, found:
1
3
18
3
ꢀ
1
16.1506 m/z; FTIR (cm ) (neat): 2934, 2852, 2811, 1653, 1525, 1250, 894, 796, 725.
-Bromo-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4k): Following general procedure, 4k was obtained
1
as a yellow oil (0.21 mmol; 59 mg, 84% yield). Rf = 0.30 (50% Acetone/Hexanes); H NMR (CDCl ,
3
500MHz): δ 8.07 (dd, J=1.8, 0.7 Hz, 1 H), 7.45 (dd, J=9.5, 0.7 Hz, 1 H), 7.25 (s, 1 H), 7.17 (dd, J=9.4, 1.9
13
Hz, 1 H), 2.89 ꢀ 3.05 (m, 4 H), 1.52 ꢀ 1.86 (m, 6 H); C NMR (CDCl , 126MHz): δ 140.0, 136.6, 126.8,
3
122.5, 121.7, 118.5, 106.7, 53.0, 26.1, 24.0; HRMS (ESI, Pos): calcd for C H BrN [M+H]+: 280.0444
1
2
14
3
ꢀ1
m/z, found: 280.0455 m/z; FTIR (cm ) (neat): 2935, 2851, 2811, 2185, 1381, 1155, 901, 791, 727.
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-Chloro-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4l): Following general procedure, 4l was obtained
1
as a colorless oil (0.12 mmol; 27 mg, 82% yield). Rf = 0.35 (10% MeOH/DCM); H NMR (CDCl ,
3
500MHz): δ 7.88 (d, J=7.2 Hz, 1 H), 7.53 (d, J=1.1 Hz, 1 H), 7.24 (br. s., 1 H), 6.76 (dd, J=7.2, 1.7 Hz, 1
13
H), 2.92 ꢀ 3.02 (m, 4 H), 1.58 ꢀ 1.82 ppm (m, 6 H); C NMR (CDCl , 176MHz): δ 148.9, 136.9, 132.5,
3
123.0, 118.5, 115.8, 114.6, 53.0, 26.0, 23.9; HRMS (ESI, Pos): calcd for C H ClN [M+H]+: 236.0949
12 15 3
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60
ꢀ
1
m/z, found: 236.0939 m/z; FTIR (cm ) (neat): 2936, 2852, 2817, 1650, 1626, 1443, 1281, 793, 731.
8
-Phenyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4m): Following general procedure, 4m was
obtained as an offꢀwhite solid (0.48 mmol; 134 mg, 76% yield). Rf = 0.32 (30% EtOAc/Petroleum Ether);
1
H NMR (CDCl , 500MHz): δ 7.92 ꢀ 8.03 (m, 3 H), 7.45 ꢀ 7.55 (m, 2 H), 7.37 ꢀ 7.44 (m, 1 H), 7.31 (s, 1 H),
3
13
7
.23 (dd, J=6.9, 1.2 Hz, 5 H), 6.88 (t, J=6.9 Hz, 1 H), 2.95 ꢀ 3.09 (m, 4 H), 1.60 ꢀ 1.89 (m, 6 H); C NMR
(CDCl , 126MHz): δ 140.5, 136.7, 136.7, 130.6, 128.9, 128.4, 128.0, 121.7, 121.4, 121.2, 111.6, 53.1,
3
2
6.2, 24.2; HRMS (ESI, Pos): calcd for C H N [M+H]+: 278.1652 m/z, found: 278.1663 m/z; mp : 96ꢀ98
18 19 3
ꢀ
1
°C; FTIR (cm ) (neat): 2929, 2829, 1450, 1367, 1300, 1147, 748, 693, 573.
8
-Methoxy-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4n): Following general procedure 4n was
1
obtained as an offꢀwhite solid (0.28 mmol; 64 mg, 81% yield). Rf = 0.37 (10% MeOH/DCM); H NMR
(
CDCl , 500MHz): δ 7.60 (dd, J=6.8, 0.7 Hz, 1 H), 7.17 (s, 1 H), 6.67 (t, J=7.2 Hz, 1 H), 6.33 ꢀ 6.43 (m, 1
3
13
H), 3.99 (s, 3 H), 2.90 ꢀ 3.05 (m, 4 H), 1.54 ꢀ 1.83 (m, 6 H); C NMR (CDCl , 126MHz): δ 149.3, 137.3,
3
1
36.1, 120.0, 115.4, 111.3, 99.3, 55.7, 53.1, 26.1, 24.1; HRMS (ESI, Pos): calcd for C H N O [M+H]+:
13 18 3
ꢀ
1
232.1444 m/z, found: 232.1453 m/z; mp : 106ꢀ110 °C; FTIR (cm ) (neat): 3038, 2927, 2915, 2847, 2805,
542, 1275, 1069, 737.
1
2-Ethyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4o): Following general procedure, 4o was obtained
1
as a brown (0.17 mmol; 38 mg, 46% yield). Rf = 0.32 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
8
.02 (dt, J=6.8, 1.2 Hz, 1 H), 7.47 (d, J=9.0 Hz, 1 H), 7.08 (ddd, J=9.0, 6.7, 1.4 Hz, 1 H), 6.74 (td, J=6.7,
13
1
.0 Hz, 1 H), 3.00 ꢀ 3.15 (m, 4 H), 2.84 (q, J=7.6 Hz, 2 H), 1.74 (br. s., 6 H), 1.36 (t, J=7.5 Hz, 3 H);
C
NMR (CDCl , 126MHz): δ 140.8, 140.0, 129.8, 123.3, 122.4, 116.7, 111.1, 52.4, 27.2, 24.1, 21.6, 14.7;
3
ꢀ
1
HRMS (ESI, Pos): calcd for C H N [M+H]+: 230.1652 m/z, found: 230.1654 m/z; FTIR (cm ) (neat):
1
4
19
3
2
932, 2850, 2812, 1557, 1501, 1347, 1223, 753, 738.
3
-(Piperidin-1-yl)imidazo[1,2-a]pyrimidine (4p): Following general procedure, 4p was obtained as a
1
dark green solid (0.27 mmol; 54 mg, 89% yield). Rf = 0.29 (10% MeOH/DCM); H NMR (CDCl , 500MHz):
3
δ 8.48 (dd, J=3.9, 2.1 Hz, 1 H), 8.25 (dd, J=6.8, 2.0 Hz, 1 H), 7.40 (s, 1 H), 6.84 (dd, J=6.8, 4.0 Hz, 1 H),
13
2
1
2
.86 ꢀ 3.12 (m, 4 H), 1.55 ꢀ 1.89 (m, 6 H); C NMR (CDCl , 126MHz): δ 148.4, 144.7, 134.6, 130.0,
3
22.7, 107.7, 52.9, 26.0, 24.0; HRMS (ESI, Pos): calcd for C H N [M+H]+: 203.1291 m/z, found:
1
1
15
4
ꢀ
1
03.1301 m/z; mp : 112ꢀ116 °C; FTIR (cm ) (neat): 3060, 2929, 2856, 2793, 2755, 1496, 839, 779, 762.
3-(Piperidin-1-yl)imidazo[1,2-a]pyrazine (4q): Following general procedure, 4q was obtained as a
1
brown solid (0.17 mmol; 34 mg, 91% yield). Rf = 0.29 (10% MeOH/DCM); H NMR (CDCl , 500MHz): δ
3
13
8.99 (d, J=1.1 Hz, 1 H), 7.75 ꢀ 7.94 (m, 2 H), 7.41 (s, 1 H), 2.93 ꢀ 3.10 (m, 4 H), 1.56 ꢀ 1.91 (m, 6 H);
C
NMR (CDCl3, 126MHz): δ 143.8, 137.2, 137.1, 128.6, 123.5, 115.4, 52.5, 25.9, 23.9; HRMS (ESI, Pos):
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2
2
2
2
2
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3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
5
6
ꢀ1
calcd for C H N [M+H]+: 203.1291 m/z, found: 203.1301 m/z; mp : 64ꢀ66 °C; FTIR (cm ) (neat): 2935,
1
1
15
4
2844, 2805, 1528, 1315, 1242, 891, 792, 610.
N-Cyclohexylimidazo[1,2-a]pyridin-3-amine (4r): Following general procedure, 4r was obtained as a
1
brown solid (0.29 mmol; 62 mg, 96% yield). Rf = 0.18 (10% MeOH/DCM); H NMR (CDCl , 400MHz): δ
3
8
.03 (d, J=7.0 Hz, 1 H), 7.51 (d, J=9.0 Hz, 1 H), 7.21 (s, 1 H), 7.09 (ddd, J=9.0, 6.7, 1.1 Hz, 1 H), 6.70 ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
0
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6
7
8
9
0
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5
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7
8
9
0
13
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.86 (m, 1 H), 2.88 ꢀ 3.08 (m, 1 H), 1.98 (d, J=9.7 Hz, 2 H), 1.55 ꢀ 1.85 (m, 3 H), 1.07 ꢀ 1.39 (m, 6 H);
C
NMR (CDCl , 126MHz): δ 140.3, 130.2, 124.9, 122.9, 118.6, 116.3, 112.5, 56.1, 33.5, 25.7, 24.8; HRMS
3
ꢀ
1
(
(
ESI, Pos): calcd for C H N [M+H]+: 216.1495 m/z, found: 216.1486 m/z; mp : 100ꢀ106 °C; FTIR (cm )
13 18 3
neat): 3174, 2995, 2921, 2852, 1565, 1365, 1120, 735, 724.
General Procedure for the Pd-Catalyzed C-H Arylation of 3-aminoimidazo[1,2-a]pyridine 4a
To a flameꢀdried 10ꢀmL microwave vial equipped with a magnetic stirrer was added dry cesium carbonate
(0.8 mmol; 2 equiv). The vial was dried in a vacuum oven at 200 °C for 16 h. After cooling of the said vial,
3
ꢀ(piperidinꢀ1ꢀyl)imidazo[1,2ꢀa]pyridine (0.4 mmol; 1 equiv) was added in the glovebox. The vial was
sealed in the glovebox and 1ꢀiodoꢀ4ꢀ(trifluoromethyl)benzene (0.8 mmol; 2 equiv) and freshly distilled
DMA (1 mL; 0.5M) were added to the reaction vessel. The resulting mixture was then heated to 150 °C
for 24 h, after which the reaction was cooled down to rt and the solids were filtered over a pad of celite.
The residue was purified using flash chromatography (0 – 50% Acetone/Hexanes, 24g column) to afford
3ꢀ(piperidinꢀ1ꢀyl)ꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)imidazo[1,2ꢀa]pyridine (5a) (75 mg; 55% yield) as a bright
1
yellow oil. Rf = 0.49 (40% Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 8.11 (d, J=7.0 Hz, 1
3
H), 8.06 (d, J=7.9 Hz, 2 H), 7.65 ꢀ 7.77 (m, 3 H), 7.23 ꢀ 7.31 (m, 1 H), 6.90 (t, J=6.7 Hz, 1 H), 3.14 (t,
13
J=5.0 Hz, 4 H), 1.55 ꢀ 1.88 (m, 6 H); C NMR (CDCl , 126MHz): δ 141.6, 138.3, 135.2, 130.9, 130.1,
3
1
9
1
29.6, 128.5, 125.1, 124.5, 123.3, 117.9, 111.9, 51.2, 26.9, 24.0; F NMR (CDCl , 471MHz): δ ꢀ62.5;
3
ꢀ1
HRMS (ESI, Pos): calcd for C H F N [M+H]+: 346.1526 m/z, found: 346.1530 m/z; FTIR (cm ) (neat):
1
9
18
3
3
2937, 2851, 1319, 1162, 1115, 1063, 847, 753, 730.
General Procedure for the Ru-Catalyzed C-H Arylation of 3-aminoimidazo[1,2-a]pyridine 4m
To a flameꢀdried 10ꢀmL microwave vial equipped with a magnetic stirrer and charged with 2m (0.1 mmol;
1
equiv) was added, in the glovebox, dry potassium carbonate (0.2 mmol; 2 equiv), 2,4,6ꢀtrimethylbenzoic
acid (0.03 mmol; 0.3 equiv), [RuCl (pꢀcymene)] (0.005 mmol, 0.05 equiv) and 4ꢀbromoacetophenone
2
2
(
0.3 mmol; 3 equiv). The vial was sealed with a septum and toluene (0.5 mL; 0.2 M) was added. The
resulting mixture was then heated at 150 °C for 15h, after which ethyl acetate was added and the mixture
was filtered over a pad of celite and concentrated under reduced pressure. The residue was purified
using flash chromatography (0 – 50% EtOAc/Hexanes, 24ꢀg column) to afford 1ꢀ(2'ꢀ(3ꢀ(piperidinꢀ1ꢀ
yl)imidazo[1,2ꢀa]pyridinꢀ8ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀyl)ethanꢀ1ꢀone (6a) (0.091 mmol; 36 mg; 91% yield) as a
1
brown solid. Rf = 0.41 (40% Acetone/Petroleum Ether); H NMR (CDCl , 500MHz): δ 7.86 (dd, J=6.1, 1.9
3
Hz, 1 H), 7.69 ꢀ 7.80 (m, 3 H), 7.45 ꢀ 7.55 (m, 3 H), 7.27 ꢀ 7.32 (m, 2 H), 7.24 (s, 1 H), 6.28 ꢀ 6.82 (m, 2
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H), 2.94 ꢀ 3.09 (m, 4 H), 2.54 (s, 3 H), 1.55 ꢀ 1.89 (m, 6 H); C NMR (CDCl , 126MHz): δ 197.9, 146.5,
3
1
1
3
40.9, 140.2, 136.5, 135.1, 135.0, 131.2, 130.3, 130.0, 129.5, 128.4, 127.9, 127.9, 124.9, 121.3, 121.0,
11.3, 53.0, 26.5, 26.1, 24.1; HRMS (ESI, Pos): calcd for C H N O [M+H]+: 396.2070 m/z, found:
2
6
25
3
ꢀ
1
96.2074 m/z; mp : 70ꢀ72 °C; FTIR (cm ) (neat): 2931, 2853, 2810, 2214, 1677, 1259, 917, 721, 594.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra, and compound characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
∆
ISHC member
*Eꢀmail: andre.charette@umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported through funding from the Natural Science and EngineeringꢀResearch Council of
Canada (NSERC) Discovery Grant RGPINꢀ2014006438, the Canada Foundationꢀfor Innovation Leaders
Opportunity Funds 227346, the Canada Research Chair Program CRCꢀ227346, theꢀ FRQNT Centre in
Green Chemistry and Catalysis (CGCC) Strategic Cluster 2014ꢀRSꢀ171310, and Université de Montréal.
S.R. and W.S.B. are both grateful to NSERC, FRQNT and Université deꢀMontréal for postgraduate
scholarships.
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