Lewis Acid-Catalyzed Denitrogenative Transannulation of Pyridotriazoles with Nitriles: Synthesis of Imidazopyridines

Article abstract of DOI:10.1021/acs.joc.6b01742

The synthesis of imidazo[1,5-a]pyridines through denitrogenative transannulation of pyridotriazoles with nitriles using BF₃·Et₂O as catalyst has been described. The combination of solvents (dichlorobenzene-dichloroethane) plays a crucial role in achieving quantitative yields of desired products under metal-free conditions.

Full text of DOI:10.1021/acs.joc.6b01742

Note
pubs.acs.org/joc
Lewis Acid-Catalyzed Denitrogenative Transannulation of
Pyridotriazoles with Nitriles: Synthesis of Imidazopyridines
Abhisek Joshi, Darapaneni Chandra Mohan, and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, Central Salt & Marine Chemicals Research Institute (CSIR), G.B. Marg, Bhavnagar,
364 002 Gujarat, India
S
* Supporting Information
ABSTRACT: The synthesis of imidazo[1,5-a]pyridines through denitrogenative transannulation of pyridotriazoles with nitriles
using BF3·Et2O as catalyst has been described. The combination of solvents (dichlorobenzene-dichloroethane) plays a crucial
role in achieving quantitative yields of desired products under metal-free conditions.
riazoles are important heterocyclic units and exhibit a
to consider. Furthermore, transition metal-catalyzed reactions
1
Twide range of biological activities. Recently, transition generate hazardous waste that is environmentally problematic;
hence, it should be avoided whenever possible. Further, the use
of benzylamines generates corresponding imines as side
products under aerobic conditions.11 In this connection,
performing the reactions under metal-free conditions is an
attractive target. Rare reports exist in the literature describing
metal-free systems for denitrogenative transannulation of
pyridotriazoles.12 Within our program on the synthesis of
fused heterocycles13 and C−H activation under metal-free
conditions,14 we have now devised a protocol for the
denitrogenative transannulation of pyridotriazoles with nitriles
using BF3·Et2O as catalyst, which we report herein (Scheme 1).
We initiated our studies by probing the reaction conditions for
the denitrogenative transannulation of pyridotriazoles with
nitriles using Lewis acid catalysts and solvents (see Table S1).
Preliminary experiments revealed that BF3·Et2O as the catalyst
and dichlorobenzene (DCB) as solvent were most effective.
The denitrogenative transannulation of pyridotriazole
occurred under metal-free reaction conditions (see Table S1)
in which a higher ratio of benzonitrile 2a was used with respect
to 3-phenyl-[1,2,3]triazolo[1,5-a]pyridine 1a to ensure a
satisfactory performance of the reaction at 150 °C in DCB as
solvent (Table 1, entries 1 and 2). Marginal improvement in
yield was observed when catalyst loading was increased to 25
mol % while decreasing the quantities of 2a and solvent (Table
1, entries 3−5). There was no advantage when dichloroethane
(DCE) was used as solvent (entry 6). Gratifyingly, a significant
enhancement in yield was observed by conducting the reaction
metal-catalyzed ring opening of 1,2,3-triazoles are well-known
for the generation of metallocarbene intermediates, and they
undergo a wide range of synthetically useful transformations
like cycloadditions, ring expansions, ylide formation, and so
forth.2,3 However, such a reaction requires precious metal salts
like Rh and Ni catalysts. Hence, the development of alternative
catalysts for such reactions is desirable. Imidazo[1,5-a]pyridines
are an important class of bridged head nitrogen heterocyclic
compounds; these scaffolds are found in many pharmacolog-
ically important compounds and included in material chemistry
like those actively probed in the context of organic light-
emitting diodes (OLED) and organic thin layer field effect
transistors (FET).4−6 However, few synthetic methods are
available for synthesizing imidazo[1,5-a]pyridines, and the
reported methods mainly rely on traditional Vilsmeier-type
cyclizations.7 Transannulation reactions have become an
indispensable tool for the synthesis of many natural products
by making or breaking of C−C and C−hetero bonds.8
Recently, Gevorgyan et al. reported the Rh(II) metal-catalyzed
denitrogenative transannulation of pyridotriazoles, which is an
efficient method for the synthesis of imidazo[1,5-a]pyridines
with nitriles. For such transformation, it is essential to have
substituents at the C-7 position (activating group (AG)) and an
electron-withdrawing group (EWG) at the C-3 position of
pyridotriazoles.9 As an alternate to rhodium, we recently
reported a copper-catalyzed transannulation of pyridotriazoles
with benzyl amines and amino acids;10 however, this method
has some drawbacks such as not being suitable for aliphatic and
heterocyclic amines. Moreover, the separation of metal catalyst
and its residual toxicity in the target compound is a central issue
Received: July 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01742
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The Journal of Organic Chemistry
Note
Scheme 1. Transannulation Reactions of Pyridotriazoles
Scheme 2. Substrate Scope of Denitrogenative
Transannulation Reactions
a
a
Table 1. Optimization of Reaction Conditions
a
Conditions: 1 (0.2 mmol), 2 (0.24 mmol), BF3·Et2O (25 mol %),
solvent {DCB (0.2 mL) + DCE (0.25 mL)} in an oil bath in a closed
tube, 120 °C, 16 h, isolated yield.
2a
catalyst
T
t
yield
(%)
entry (eq)
(mol %)
solvent (mL)
DCB (1)
(°C) (h)
1
10
10
3
BF3(OEt2)
(10)
150
150
150
140
140
120
120
120
120
120
4
30
52
65
64
63
50
98
15
45
98
2
BF3(OEt2)
(20)
DCB (1)
4
corresponding transannulated products 3a−k in moderate to
excellent yields (43−98%). Similarly, the presence of electron-
donating and -withdrawing groups at either the ortho or meta
position of benzonitriles provided the corresponding trans-
annulated products (3l−u) in good yields (61−91%). The
presence of 2,6-dichloro-ortho substituents also gave desired
product 3v in 60% yield. As evident from the yields of products
3b−v, the electronic effects associated with electron-donating
or -withdrawing substituents on the benzonitrile do not affect
the efficiency of the transformation.
3
BF3(OEt2)
(25)
DCB (0.5)
DCB (0.25)
DCB (0.25)
DCE (1)
4
4
3
BF3(OEt2)
(25)
4
5
3
BF3(OEt2)
(25)
4
6
3
BF3(OEt2)
(25)
12
10
12
12
10
7
3
BF3(OEt2)
(25)
DCB (0.2) +
DCE (0.25)
The versatile metal-free denitrogenative transannulation was
not limited to the benzonitrile substrates. Indeed, the
benzonitriles bearing extended aromatics, such as [1,1′-
biphenyl]-4-carbonitrile, 4′-methyl-[1,1′-biphenyl]-4-carboni-
trile, and anthracene-9-carbonitrile, proved to be amenable to
this procedure and afford the differently decorated products
3w−y in good yields. The scope with regard to the benzonitrile
coupling partner was also extended toward heterocycles. The
reactions of 1a with thiophene-2-carbonitrile, thiophene-3-
carbonitrile, and 3-oxo-1,3-dihydroisobenzofuran-1-carbonitrile
were also tolerated and gave desired products 3z, 3aa, and 3ab
in 68, 89, and 63% yields, respectively. Thus, this demonstrates
the potential utility of this methodology for the synthesis of
medicinally relevant scaffolds.
To further expand the scope of the methodology, we
evaluated the denitrogenative transannulation reaction of
chloro-substituents in the pyridotriazole derivatives with
representative nitriles under the optimized conditions. The 3-
(4-chlorophenyl)-[1,2,3]triazolo[1,5-a]pyridine reacts with ar-
omatic, aliphatic, and heteroaromatic nitriles to produce the
corresponding imidazo[1,5-a]pyridines 3ac−ag in good to
quantitative yields.
8
3
BF3(OEt2)
(10)
DCB (0.2) +
DCE (0.25)
9
1.2 BF3(OEt2)
(20)
DCB (0.2) +
DCE (0.25)
10
1.2 BF3(OEt2)
(25)
DCB (0.2) +
DCE (0.25)
a
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst, solvent in an
oil bath, closed tube, isolated yield.
with the combination of DCB and DCE as solvent (entry 7).
With this solvent combination, decreasing the catalyst loading
to 10 and 20 mol % did not result in any improvement of yield
(Table 1, entries 8 and 9). Further optimization allowed us to
reduce the amount of 2a to 1.2 equiv without any loss of yield
(entry 10).
With this set of optimized conditions (Table 1, entry 10), the
denitrogenative transannulation of pyridotriazole with different
nitriles was examined (Scheme 2). The results in Scheme 2
demonstrate the versatility of the reaction with a high degree of
functional group tolerance and with a broad substrate scope.
Initially, benzonitrile bearing electron-donating and -with-
drawing groups (Me, OMe, halogens, NO2, CF3, CN, and
CO2Me) at the para position could react with 3-phenyl-
[1,2,3]triazolo[1,5-a]pyridine (1a) smoothly to afford the
The successful transformation of denitrogenative trans-
annulation of pyridotriazole under metal-free conditions
B
DOI: 10.1021/acs.joc.6b01742
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The Journal of Organic Chemistry
Note
prompted us to investigate the generality of this method toward
aliphatic nitrile substrates. Thus, syntheses of alkyl-aryl
imidazo[1,5-a]pyridines 4 were carried out by reacting 1a
with different alkyl nitriles 2 (Scheme 3). It is remarkable to
Scheme 5. Control Experiments
Scheme 3. Denitrogenative Transannulation of 1a with Alkyl
a
Nitriles
pathway. Another reaction was performed with 2-benzoylpyr-
idine 6 instead of pyridotriazole 1a under the optimized
conditions to know whether the reaction proceeds through
intermediate 6 by the hydrolysis of pyridotriazole (Scheme 5,
eq 2). Interestingly, a trace amount of product 3a formation
was observed. This experiment clearly suggests that the reaction
may proceed via α-imino diazo compound formation followed
by cyclization to give the desired product.
On the basis of these observations and our previous results
on imidazo[1,5-a]pyridines,10 a plausible reaction mechanism
has been proposed for this transformation (Scheme 6). Initially,
a
Conditions: 1a (0.2 mmol), 2 (0.24 mmol), solvent {DCB (0.2 mL)
Scheme 6. Plausible Mechanism
+ DCE (0.25 mL)} in an oil bath in a closed tube, 16 h, isolated yield.
note that the simple aliphatic nitriles, such as acetonitrile and
branched pivalonitrile, and long chain nitriles, such as pentane
nitrile and octane nitrile, were also competent reactants under
the optimized conditions and produced the corresponding
imidazo[1,5-a]pyridines 4a−d in good to excellent yields. To
our delight, we found this transformation to be very general for
a wide range of nitriles, such as 2-phenylacetonitrile, 2-(o-
tolyl)acetonitrile, 2-(naphthalen-1-yl)acetonitrile), and 2-(cy-
clohex-1-en-1-yl)acetonitrile, and produced corresponding
products 4e−h in good yields.
To validate the process for scale up studies, we performed
the reaction of 1a with benzonitrile, thiophene-3-carbonitrile,
and pentane nitrile and obtained corresponding products 3a,
3aa, and 4c in 78% (1.079 g), 73% (0.950 g), and 74% (1.03 g)
yields, respectively, under the optimized conditions. This study
indicates the feasibility of the method for industrial/commercial
production (Scheme 4).
Scheme 4. Scale Up Studies
triazolo[1,5-a]pyridine at high temperature will be in
equilibrium with α-imino diazo compound A; its reaction
with BF3 would generate the intermediates B/C.15 Product 3
may be obtained by either path (a) or path (b) from
intermediate C. In path (a), nucleophilic substitution at the
sp2 carbon of C with nitrile derivative may generate
intermediate D, and its cyclization will give desired product 3
by the elimination of BF3. On the other hand, [3 + 2]
cycloaddition of C with nitrile generates another intermediate E
[path (b)]. Denitrogenation and simultaneous elimination of
BF3 from E afford desired product 3.
To gain insight into the reaction mechanism, we performed
some control experiments (Scheme 5). Initially, the reaction
was conducted by the addition of radical scavenger TEMPO
under optimized conditions to know whether the reaction
proceeds via radical or ionic path (Scheme 5, eq 1). Under
these conditions, no TEMPO adduct 5 formation was observed.
It indicates that the reaction does not proceed via the radical
CONCLUSIONS
■
In summary, we have developed an efficient method for the
synthesis of imidazo[1,5-a]pyridines denitrogenative trans-
annulation of pyridotriazoles with nitriles using BF3·Et2O as
catalyst. The combination of solvents (dichlorobenzene-
dichloroethane) is essential to achieve quantitative yields of
C
DOI: 10.1021/acs.joc.6b01742
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Note
3-(4-Methoxyphenyl)-1-phenylimidazo[1,5-a]pyridine (3c).10 Elu-
ent, 5% EtOAc/hexane; 74% yield (44.1 mg); solid; H NMR (500
desired products under metal-free conditions. The commer-
cially available nitriles with a wide range of substituted
benzonitriles, aliphatic, branched aliphatic, cyclic, biphenyl,
anthracene, and thiophene nitriles, including acetonitrile and 3-
oxo-1,3-dihydroisobenzofuran-1-carbonitrile, were amenable to
this procedure.
1
MHz, CDCl3) δ 8.03 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H),
7.70 (d, J = 9.0 Hz, 1H) 7.64 (d, J = 8.5 Hz, 2H), 7.37 (t, J = 7.5 Hz,
2H), 7.20 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.63 (dd, J =
9.0 Hz, J = 6.0 Hz, 1H), 6.41 (t, J = 6.5 Hz, 1H), 3.75 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 159.9, 138.0, 135.0, 131.5, 130.9, 129.6,
128.6, 127.2, 126.6, 126.3, 122.5, 121.6, 119.3, 118.9, 114.3, 112.9,
55.3; mp 159−161 °C.
EXPERIMENTAL SECTION
■
General. All commercially available chemicals and reagents were
1
used without any further purification unless otherwise indicated. H
and 13C NMR spectra were recorded at 500 and 125 MHz,
respectively. The spectra were recorded in CDCl3 and DMSO-d6 as
solvent. Multiplicity is indicated as follows: s (singlet), d (doublet), t
(triplet), m (multiplet), dd (doublet of doublets), and so forth, and
coupling constants (J) are given in Hz. Chemical shifts are reported in
ppm relative to TMS as an internal standard. The peaks around delta
3-(4-Bromophenyl)-1-phenylimidazo[1,5-a]pyridine (3d). Eluent,
1
1
values of H NMR (7.2) and 13C NMR (77.0) correspond to the
5% EtOAc/hexane; 81% yield (56.5 mg); solid; H NMR (500 MHz,
1
deuterated solvent chloroform and H NMR (2.50) and 13C NMR
CDCl3) δ 8.08 (d, J = 7.0 Hz, 1H), 7.83−7.82 (m, 2H), 7.75 (d, J = 9.0
Hz, 1H), 7.63−7.61 (m, 2H), 7.57−7.55 (m, 2H), 7.39 (t, J = 7.5 Hz,
2H), 7.23 (dd, J = 14.0 Hz, J = 0.5 Hz, 1H), 6.71 (dd, J = 9.0 Hz, J =
6.5 Hz, 1H), 6.51 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
136.8, 134.6, 132.3, 132.1, 129.6, 129.0, 128.7, 127.8, 126.7, 126.4,
122.7, 121.4, 119.8, 119.1, 113.5; HRMS calcd for C19H14N2Br [M +
H+] 349.0340, found 349.0331; mp 179−181 °C.
(39.43) correspond to the deuterated solvent DMSO, respectively.
Mass spectra were obtained using the electron impact (EI) ionization
method. Progress of the reactions was monitored by thin layer
chromatography (TLC). All products were purified through column
chromatography using silica gel with 100−200 mesh size using
hexane/ethyl acetate as eluent unless otherwise indicated.
General Procedure for the Synthesis of Imidazo[1,5-
a]pyridine (3a). To a reaction tube equipped with a magnetic stir
bar were added DCE (0.25 mL), BF3·OEt2 (40−50% purity, 25 mol
%), 3-phenyl-[1,2,3]triazolo[1,5-a]pyridine 1a (39.0 mg, 0.2 mmol),
benzonitrile 2a (25.68 mg, 0.24 mmol), and 0.2 mL of 1,2-
dichlorobenzene. The mixture was heated in an oil bath at 120 °C
in a closed tube. The reaction was monitored by TLC; after
completion, the solution was allowed to cool to room temperature.
Then, the mixture was poured into 30 mL of sodium chloride solution.
The product was extracted with EtOAc (15 mL × 3) and dried with
anhydrous Na2SO4. Removal of the solvent under reduced pressure
left the residue, which was purified by column chromatography using
silica gel (4% EtOAc/hexane) to afford 3a (53.0 mg, 98% yield).
Characterization Data. 1,3-Diphenylimidazo[1,5-a]pyridine
3-(4-Chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3e).10 Elu-
ent, 4% EtOAc/hexane; 90% yield (55.1 mg); solid; H NMR (500
1
MHz, CDCl3) δ 8.07 (d, J = 7.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H),
7.74 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.40 (dd, J = 18.0
Hz, J = 7.5 Hz, 4H), 7.22 (t, J = 7.0 Hz, 1H), 6.70 (dd, J = 9.0 Hz, J =
6.5 Hz, 1H), 6.49 (t, J = 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
136.8, 134.7, 134.5, 132.2, 129.3, 129.2, 128.7, 128.6, 127.8, 126.7,
126.6, 121.4, 119.7, 119.1, 113.5; mp 181−183 °C.
(3a).10 Eluent, 4% EtOAc/hexane; 98% yield (53.0 mg); solid; H
1
NMR (500 MHz, CDCl3) δ 8.24 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 7.5
Hz, 2H), 7.84−7.83 (m, 3H), 7.55 (t, J = 7.5 Hz, 2H), 7.48−7.43 (m,
3H), 7.31 (t, J = 7.5 Hz, 1H), 6.79 (dd, J = 9.0 Hz, J = 6.5, 1H), 6.58
(t, J = 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.0, 134.9,
131.9, 130.1, 128.9, 128.7, 128.6, 128.3, 127.6, 126.7, 126.5, 121.7,
119.6, 119.1, 113.2; mp 115−117 °C.
3-(4-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3f).10 Eluent,
1
4% EtOAc/hexane; 88% yield (50.4 mg); semisolid; H NMR (500
MHz, CDCl3) δ 8.05 (dd, J = 7.0 Hz, J = 0.5 Hz, 1H), 7.84 (d, J = 8.0
Hz, 2H), 7.75−7.70 (m, 3H), 7.39 (t, J = 7.5 Hz, 2H), 7.22−7.19 (m,
1H), 7.16−7.11 (m, 2H), 6.70−7.67 (m, 1H), 6.49 (t, J = 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 163.8 (d, J = 247.6 Hz), 137.0, 134.8,
131.9, 130.2 (d, J = 7.8 Hz,), 128.6, 127.5, 126.7, 126.5, 126.3, 121.4,
119.6, 119.1, 116.1 (d, J = 21.6 Hz), 113.3; mp 159−161 °C.
1-Phenyl-3-(p-tolyl)imidazo[1,5-a]pyridine (3b).10 Eluent, 4%
EtOAc/hexane; 90% yield (52.2 mg); solid; 1H NMR (500 MHz,
CDCl3) δ 8.20 (d, J = 7.0 Hz, 1H), 7.94 (dd, J = 8.5 Hz, J = 1.0 Hz,
2H), 7.83 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 8.0
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 6.77−6.74
(m, 1H), 6.55 (dd, J = 10.0 Hz, J = 3.5 Hz, 1H), 2.43 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 138.7, 138.2, 135.0, 131.7, 129.6, 128.6,
128.2, 127.4, 127.2, 126.7, 126.4, 121.8, 119.4, 119.0, 113.0, 21.3; mp
137−139 °C.
3-(4-Iodophenyl)-1-phenylimidazo[1,5-a]pyridine (3g). Eluent,
4% EtOAc/hexane; 43% yield (34.3 mg); solid; 1H NMR (500
MHz, CDCl3) δ 8.20 (d, J = 7.5 Hz, 1H), 7.92−7.90 (m, 2H), 7.87 (t,
J = 8.5 Hz, 3H), 7.60 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.32
(t, J = 7.5 Hz, 1H), 6.82−6.79 (m, 1H), 6.61 (dd, J = 7.5 Hz, J = 1.0
D
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Note
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.1, 136.9, 134.7, 132.4,
129.7, 128.7, 127.9, 126.8, 126.6, 121.5, 119.8, 119.2, 113.6, 94.3;
HRMS calcd for C19H14N2I [M + H+] 397.0202, found 397.0193; mp
181−183 °C.
1-Phenyl-3-(m-tolyl)imidazo[1,5-a]pyridine (3l).10 Eluent, 4%
EtOAc/hexane; 88% yield (50.0 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 8.21 (dd, J = 7.0 Hz, J = 0.5 Hz, 1H), 7.94 (dd, J = 8.0
Hz, J = 1.0 Hz, 2H), 7.81−7.79 (m, 1H), 7.66 (s, 1H), 7.60 (d, J = 8.0
Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.30−7.23
(m, 2H), 6.75−6.72 (m, 1H), 6.54 (t, J = 6.5 Hz, 1H), 2.43 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 138.8, 138.2, 134.9, 131.8 129.9,
129.1, 128.7, 128.6, 127.5, 126.7, 126.4, 125.0, 121.7 119.5, 119.0,
113.0, 21.4.
3-(4-Nitrophenyl)-1-phenylimidazo[1,5-a]pyridine (3h).16 Eluent,
15% EtOAc/hexane; 81% yield (51.1 mg); solid; 1H NMR (500 MHz,
CDCl3) δ 8.38 (dd, J = 14.0 Hz, J = 7.0 Hz, 3H), 8.08 (d, J = 8.5 Hz,
2H), 7.92 (t, J = 7.0 Hz, 3H), 7.50 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5
Hz, 1H), 6.92 (dd, J = 8.5 Hz, J = 7.0 Hz, 1H), 6.74 (t, J = 6.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 147.0, 136.3, 135.5, 134.2,
133.7, 133.4, 129.0, 128.8, 128.0, 127.1, 126.8, 124.3, 121.5, 120.7,
119.5, 114.5; mp 189−191 °C.
3-(3-Methoxyphenyl)-1-phenylimidazo[1,5-a]pyridine (3m).10
Eluent, 5% EtOAc/hexane; 68% yield (40.7 mg); semisolid; 1H
NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.5
Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.36 (dd, J = 15.5 Hz, J = 4.0 Hz,
2H), 7.32 (d, J = 8.0 Hz, 1H), 7.29−7.28 (m, 2H), 7.21 (t, J = 7.5 Hz,
1H), 6.89 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 9.0 Hz, J = 6.5 Hz, 2H),
6.45 (t, J = 6.5 Hz, 1H), 3,37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
160.0, 137.8, 134.8, 131.8, 131.2, 129.8, 128.6, 127.6, 126.7, 126.4,
121.8, 120.2, 119.6, 118.9, 114.7, 113.6, 113.1, 55.3.
1-Phenyl-3-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine
(3i).10 Eluent, 4% EtOAc/hexane; 76% yield (51.2 mg); solid; 1H
NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 8.0
Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 1H), 7.78 (d, J
= 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 6.84
(dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.64 (t, J = 6.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 136.4, 134.5, 133.6, 132.7, 130.4, 130.1, 128.7,
128.2, 128.1, 126.8, 125.9, 125.0, 122.8, 121.4, 120.1, 119.3, 113.8; mp
140−142 °C.
3-(3-Bromophenyl)-1-phenylimidazo[1,5-a]pyridine (3n). Eluent,
1
4% EtOAc/hexane; 70% yield (48.6 mg); semisolid; H NMR (500
MHz, CDCl3) δ 8.20 (d, J = 7.5 Hz, 1H), 8.0 (s, 1H), 7.92 (d, J = 7.5
Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.56 (d, J
= 8.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.31
(t, J = 7.0 Hz, 1H), 6.80 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.61 (t, J =
7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 136.3, 134.6, 132.3,
132.1, 131.6, 131.0, 128.7, 127.9, 126.7, 126.6, 126.4, 123.0, 121.4,
119.9, 119.1, 113.6; HRMS calcd for C19H14N2Br [M + H+] 349.0340,
found 349.0337.
4-(1-Phenylimidazo[1,5-a]pyridin-3-yl)benzonitrile (3j). Eluent,
15% EtOAc/hexane; 62% yield (36.9 mg); semisolid; H NMR (500
1
MHz, CDCl3) δ 8.30 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H),
7.92 (t, J = 8.0 Hz, 3H), 7.81 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 8.0 Hz,
2H), 7.35 (t, J = 7.5 Hz, 1H), 6.90 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H),
6.71 (t, J = 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 135.8, 134.4,
133.3, 132.7, 128.8, 128.7, 128.0, 127.0, 126.8, 121.4, 120.5, 119.4,
118.6, 114.3, 111.6; HRMS calcd for C20H14N3 [M + H+] 296.1188,
found 296.1187.
3-(3-Chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3o).10 Elu-
ent, 4% EtOAc/hexane; 69% yield (41.2 mg); semisolid; H NMR
1
(500 MHz, CDCl3) δ 8.21 (d, J = 7.0 Hz, 1H), 7.92 (dd, J = 7.5 Hz, J
= 1.0 Hz, 2H), 7.85−7.82 (m, 2H), 7.72 (dd, J = 7.5 Hz, J = 1.5 Hz,
1H), 7.48−7.43 (m, 3H), 7.41−7.39 (m, 1H), 7.32−7.28 (m, 1H),
6.81−6.78 (m, 1H), 6.61−6.58 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 136.4, 134.9, 134.6, 132.3, 131.8, 130.2, 128.7, 128.2, 127.9,
126.7, 126.6, 126.0, 121.5, 119.9, 119.1, 113.6.
Methyl 4-(1-phenylimidazo[1,5-a]pyridin-3-yl)benzoate (3k). Elu-
1
ent, 10% EtOAc/hexane; 76% yield (50.1 mg); solid; H NMR (500
MHz, CDCl3) δ 8.18 (d, J = 7.0 Hz, 1H), 8.09 (d, J = 8.5 Hz, 2H),
7.85 (t, J = 8.5 Hz, 4H), 7.75 (d, J = 9.5 Hz, 1H), 7.39 (t, J = 7.5 Hz,
2H), 7.23 (t, J = 7.5 Hz, 1H), 6.73 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H),
6.53 (t, J = 6.5 Hz, 1H), 3.56 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
166.5, 136.7, 134.5, 134.3, 132.7, 130.1, 129.6, 128.6, 128.2, 127.6,
126.77, 126.71, 121.6, 120.1, 119.1, 113.8, 25.1; HRMS calcd for
C21H17N2O2 [M + H+] 329.1290, found 329.1297; mp 189−191 °C.
E
DOI: 10.1021/acs.joc.6b01742
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3-(3-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3p).10 Elu-
ent, 4% EtOAc/hexane; 91% yield (52.3 mg); solid; H NMR (500
1H), 7.29 (t, J = 7.0 Hz, 1H), 6.83 (dd, J = 9.5 Hz, J = 6.5 Hz, 1H),
6.59 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 135.6, 134.8,
134.2, 133.3, 131.5, 130.7, 129.8, 129.2, 128.6, 127.1, 126.6, 126.4,
122.5, 119.8, 118.7, 112.7; HRMS calcd for C19H14N2Cl [M + H+]
305.0846, found 305.0834.
1
MHz, CDCl3) δ 8.24 (d, J = 7.5 Hz, 1H), 7.93−7.91 (m, 2H), 7.85 (d,
J = 9.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.58−7.55 (m, 1H), 7.51−
7.45 (m, 3H), 7.32 (t, J = 7.0 Hz, 1H), 8.15 (td, J = 8.5 Hz, J = 2.0 Hz,
1H), 6.82 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.62 (t, J = 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 164.0 (d, J = 245.3 Hz), 136.6, 134.6,
132.3, 132.2, 132.1, 130.6 (d, J = 8.2 Hz), 128.7, 127.9, 126.7, 126.6,
123.6, 121.5, 119.9, 119.2, 115.7 (d, J = 21.0 Hz), 115.3 (d, J = 22.6
Hz), 113.6; mp 93−95 °C.
3-(2-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3u).10 Elu-
1
ent, 4% EtOAc/hexane; 81% yield (46.9 mg); solid; H NMR (500
MHz, CDCl3) δ 7.94 (dd, J = 7.5 Hz, J = 1.0 Hz, 2H), 7.87 (d, J = 9.0
Hz, 1H), 7.82 (td, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.77−7.75 (m, 1H),
7.49 (td, J = 7.0 Hz, J = 1.5 Hz, 3H), 7.34−7.28 (m, 2H), 7.26−7.22
(m, 1H), 6.84−6.81 (m, 2H), 6.62−6.59 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 161.0 (d, J = 247.6 Hz), 134.8, 133.3, 132.5, 132.2,
131.0 (d, J = 8.8 Hz), 128.6, 127.8, 126.7, 126.5, 124.9, 122.6 (d, J =
5.8 Hz), 119.9, 118.7, 118.1, 117.9, 116.1 (d, J = 21.0 Hz), 112.9; mp
93−95 °C.
3-(3-Nitrophenyl)-1-phenylimidazo[1,5-a]pyridine (3q).16 Eluent,
10% EtOAc/hexane; 83% yield (51.9 mg); solid; 1H NMR (500 MHz,
CDCl3) δ 8.71(s, 1H), 8.26 (dd, J = 7.0 Hz, J = 5.0 Hz, 2H), 8.22 (d, J
= 8.0 Hz, 1H), 7.92 (t, J = 7.5 Hz, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.70
(t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H),
6.88 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.70 (t, J = 6.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 148.5, 135.2, 134.3, 133.7, 132.9, 131.8,
130.0, 128.7, 128.4, 126.9, 126.3, 123.0, 122.3, 121.1, 120.3, 119.3,
114.3; mp 169−171 °C.
3-(2,6-Dichlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3v). Elu-
1
ent, 4% EtOAc/hexane; 60% yield (40.9 mg); semisolid; H NMR
(500 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 9.5 Hz,
1H), 7.48−7.37 (m, 6H), 7.30 (dd, J = 7.5 Hz, J = 7.0 Hz, 1H), 6.88
(dd, J = 8.5 Hz, J = 7.5 Hz, 1H), 6.60 (t, J = 6.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 137.6, 134.8, 132.4, 131.6, 128.6, 128.3, 128.2,
126.7, 126.6, 126.4, 121.5, 120.0, 118.9, 113.2; HRMS calcd for
C19H13N2Cl2 [M + H+] 339.0456, found 339.0443.
3-(2-Methoxyphenyl)-1-phenylimidazo[1,5-a]pyridine (3r).10 Elu-
ent, 4% EtOAc/hexane; 80% yield (48.0 mg); semisolid; H NMR
1
(500 MHz, CDCl3) δ 7.96 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 9.5 Hz,
1H), 7.68 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H),
7.47−7.43 (m, 3H), 7.28 (dd, J = 15.0 Hz, J = 5.5 Hz, 1H), 7.12 (t, J =
7.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 9.5 Hz, J = 6.5 Hz,
1H), 6.53 (t, J = 6.5 Hz, 1H), 3.79(s, 3H); 13C NMR (125 MHz,
CDCl3) δ 157.3, 136.1, 135.1, 132.7, 131.3, 130.0, 128.5, 127.3, 126.6,
126.1, 123.4, 121.1, 119.4, 119.0, 118.5, 118.3, 118.2, 111.9, 111.1,
55.4.
3-([1,1′-Biphenyl]-4-yl)-1-phenylimidazo[1,5-a]pyridine (3w). Elu-
1
ent, 2% EtOAc/hexane; 62% yield (42.5 mg); semisolid; H NMR
(500 MHz, CDCl3) δ 8.28 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 7.5 Hz,
2H), 7.92 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.0
Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 4H), 7.39 (t, J =
7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.79 (dd, J = 9.5 Hz, J = 6.0 Hz,
1H), 6.59 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 141.4,
140.3, 137.7, 134.8, 132.1, 130.9, 128.8, 128.6, 128.5, 127.7, 127.6,
127.0, 126.7, 126.5, 121.8, 119.7, 119.1, 113.3; HRMS calcd for
C25H19N2 [M + H+] 347.1548, found 347.1558.
3-(2-Bromophenyl)-1-phenylimidazo[1,5-a]pyridine (3s). Eluent,
4% EtOAc/hexane; 61% yield (42.6 mg); semisolid; H NMR (500
1
MHz, CDCl3) δ 7.96 (dd, J = 8.5 Hz, J = 0.5 Hz, 2H), 7.87 (d, J = 9.5
Hz, 1H), 7.72 (dd, J = 8.0 Hz, J = 0.5 Hz, 1H), 7.62 (dd, J = 7.5 Hz, J
= 2.0 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 3H), 7.37
(td, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 6.83−6.80
(m, 1H), 6.58−6.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 136.7,
134.8, 133.4, 133.0, 131.3, 131.2, 131.0, 128.6, 127.6, 126.9, 126.6,
126.3, 124.2, 122.4, 119.8, 118.7, 112.7; HRMS calcd for C19H14N2Br
[M + H+] 349.0340, found 349.0337.
3-(4′-Methyl-[1,1′-biphenyl]-4-yl)-1-phenylimidazo[1,5-a]-
pyridine (3x). Eluent, 2% EtOAc/hexane; 63% yield (45.2 mg); solid;
1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.0 Hz, 1H), 7.96−7.94
(m, 2H), 7.91−7.89 (m, 2H), 7.86 (d, J = 9.0 Hz, 1H), 7.75−7.74 (m,
2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.32 (dd, J =
13.5 Hz, J = 8.0 Hz, 3H), 6.81 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.60−
6.57 (m, 1H), 2.41(s, 3H); 13C NMR (125 MHz, CDCl3) δ 141.4,
137.5, 129.6, 128.7, 128.5, 127.7, 127.4, 126.88, 126.81, 126.5, 121.8,
119.6, 119.1, 113.2, 21.1; HRMS calcd for C26H21N2 [M + H+]
361.1705, found 361.1703; mp 159−161 °C.
3-(2-Chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3t).10 Elu-
ent, 4% EtOAc/hexane; 68% yield (40.8 g); semisolid; 1H NMR
(500 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 9.0 Hz,
1H), 7.67 (dd, J = 7.0 Hz, J = 2.0 Hz, 1H), 7.58−7.56 (m, 1H), 7.54
(dd, J = 7.0 Hz, J = 1.0 Hz, 1H), 7.47−7.43 (m, 3H), 7.42−7.39 (m,
F
DOI: 10.1021/acs.joc.6b01742
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1-(4-Chlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3ac). Eluent,
1
4% EtOAc/hexane; 97% yield (59.5 mg); solid; H NMR (500 MHz,
CDCl3) δ 8.19 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.79 (d, J
= 8.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H),
7.44−7.38 (m, 3H), 6.77 (dd, J = 9.0 Hz, J = 6.5, 1H), 6.54 (t, J = 6.5
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.1, 133.4, 132.4, 131.9,
130.5, 129.8, 128.9, 128.8, 128.7, 128.1, 127.7, 121.7, 120.0, 118.6,
113.2; HRMS calcd for C19H14N2Cl [M + H+] 305.0846, found
305.0850; mp 177−179 °C.
3-(Anthracen-9-yl)-1-phenylimidazo[1,5-a]pyridine (3y). Eluent,
10% EtOAc/hexane; 69% yield (50.8 mg); solid; 1H NMR (500 MHz,
CDCl3) δ 8.63 (s, 1H), 8.09 (dd, J = 7.5 Hz, J = 7.5 Hz, 4H), 8.00 (d, J
= 9.5 Hz, 1H), 7.52−7.45 (m, 6H), 7.40−7.37 (m, 2H), 7.32 (t, J = 7.5
Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H), 6.84 (dd, J = 9.0 Hz, J = 6.5 Hz,
1H), 6.39 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 135.1,
131.8, 131.4, 129.4, 128.7, 127.0, 126.9, 126.6, 126.4, 125.6, 125.4,
122.1, 119.9, 118.9, 112.8; HRMS calcd for C27H19N2 [M + H+]
371.1548, found 371.1566; mp 209−211 °C.
1-(4-Chlorophenyl)-3-(2-fluorophenyl)imidazo[1,5-a]pyridine
1
(3ad). Eluent, 4% EtOAc/hexane; 98% yield (64.0 mg); solid; H
NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H), 7.80−7.75 (m,
3H), 7.50−7.45 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 7.5 Hz,
1H), 7.26−7.22 (m, 1H), 6.86 (dd, J = 8.5 Hz, J = 7.0, 1H), 6.62 (t, J =
6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 161.0 (d, J = 248.1 Hz),
133.5, 133.3, 132.4, 132.0, 131.2 (d, J = 7.8 Hz), 131.0, 128.8, 127.9,
127.7, 124.9, 122.77, 122.73, 120.3, 118.4, 117.9, 117.7, 116.1 (d, J =
21.2 Hz), 113.0; HRMS calcd for C19H13N2FCl [M + H+] 323.0751,
found 323.0739; mp 155−157 °C.
1-Phenyl-3-(thiophen-2-yl)imidazo[1,5-a]pyridine (3z). Eluent,
5% EtOAc/hexane; 68% yield (37.8 mg); solid; 1H NMR (500
MHz, CDCl3) δ 8.30 (d, J = 7.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H),
7.82 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.47−7.41 (m, 3H),
7.31 (t, J = 7.5 Hz, 1H), 7.18 (dd, J = 3.5 Hz, J = 3.5 Hz, 1H), 6.79
(dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.64 (t, J = 6.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 134.5, 132.5, 132.1, 132.0, 128.6, 127.7, 127.5,
126.8, 126.6, 126.1, 125.2, 121.9, 119.6, 119.0, 113.7; HRMS calcd for
C17H13N2S [M + H+] 277.0799, found 277.0811; mp 87−89 °C.
1-(4-Chlorophenyl)-3-(2-methylbenzyl)imidazo[1,5-a]pyridine
(3ae). Eluent, 4% EtOAc/hexane; 71% yield (47.0 mg); semisolid; 1H
NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 9.5
Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.19 (t, J =
7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.80 (d,
J = 7.5 Hz, 1H), 6.73 (dd, J = 9.5 Hz, J = 6.5 Hz, 1H), 6.46 (t, J = 6.5
Hz, 1H), 4.41 (s, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
136.6, 136.4, 134.1, 133.6, 131.6, 130.5, 129.0, 128.7, 128.0, 127.5,
126.9, 126.2, 121.3, 119.3, 118.6, 112.6, 31.2, 19.7; HRMS calcd for
C21H18N2Cl [M + H+] 333.1159, found 333.1165.
1-Phenyl-3-(thiophen-3-yl)imidazo[1,5-a]pyridine (3aa). Eluent,
4% EtOAc/hexane; 89% yield (49.0 mg); solid; H NMR (500 MHz,
1
CDCl3) δ 8.16 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.0 Hz, 2H), 7.80 (d, J
= 9.0 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 5.0 Hz, 1H),
7.47−7.43 (m, 3H), 7.30 (t, J = 7.0 Hz, 1H), 6.75 (dd, J = 9.5 Hz, J =
6.0 Hz, 1H), 6.57 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
134.8, 134. 2, 131.5, 130.8, 128.6, 127.4, 127.2, 126.7, 126.4, 126.3,
123.3, 121.7, 119.4, 118.9, 113.3; HRMS calcd for C17H13N2S [M +
H+] 277.0799, found 277.0802; mp 104−106 °C.
3-Butyl-1-(4-chlorophenyl)imidazo[1,5-a]pyridine (3af). Eluent,
5% EtOAc/hexane; 95% yield (54.0 mg); solid; 1H NMR (500
MHz, CDCl3) δ 7.79−7.78 (m, 1H), 7.77−7.76 (m, 1H), 7.71 (dd, J =
14.0 Hz, J = 9.5 Hz, 2H), 7.38−7.36 (m, 2H), 6.72 (dd, J = 9.5 Hz, J =
6.0 Hz, 1H), 6.55 (t, J = 6.5 Hz, 1H), 3.01 (t, J = 7.5 Hz, 2H), 1.85−
1.79 (m, 2H), 1.50−1.43 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 139.1, 133.7, 131.5, 128.7, 127.4, 126.4, 121.0,
118.9, 118.6, 112.4, 29.1, 26.3, 22.5, 13.7; HRMS calcd for C17H18N2Cl
[M + H+] 285.1159, found 285.1152; mp 69−71 °C.
3-(1-Phenylimidazo[1,5-a]pyridin-3-yl)isobenzofuran-1(3H)-one
(3ab). Eluent, 20% EtOAc/hexane; 63% yield (40.8 mg); semisolid;
1H NMR (500 MHz, CDCl3) δ 7.97 (t, J = 6.5 Hz, 3H), 7.91−7.83
(m, 3H), 7.76 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.49 (t, J =
7.5 Hz, 3H), 7.33 (t, J = 7.0 Hz, 1H), 6.90 (dd, J = 9.0 Hz, J = 6.5 Hz,
1H), 6.69 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.5,
135.0, 130.5, 129.3, 128.5, 128.4, 126.8, 126.5, 126.1, 122.5, 119.0,
118.8, 112.3, 27.9, 25.4, 22.5, 21.8; HRMS calcd for C21 H15N2O2 [M
+ H+] 327.1134, found 327.1134.
G
DOI: 10.1021/acs.joc.6b01742
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1-(4-Chlorophenyl)-3-(thiophen-3-yl)imidazo[1,5-a]pyridine
(3ag). Eluent, 4% EtOAc/hexane; 99% yield (61.7 mg); solid; 1H
NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.5
Hz, 2H), 7.78−7.75 (m, 2H), 7.62 (d, J = 5.0 Hz, 1H), 7.51 (dd, J =
4.5 Hz, J = 3.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 9.0 Hz,
J = 6.5 Hz, 1H), 6.64 (t, J = 6.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 134.5, 133.4, 132.0, 130.7, 130.4, 128.8, 127.8, 127.4, 126.5,
123.6, 122.0, 119.9, 118.8, 113.4; HRMS calcd for C17H12N2SCl [M +
H+] 311.0410, found 311.0401; mp 187−189 °C.
3-Benzyl-1-phenylimidazo[1,5-a]pyridine (4e). Eluent, 10%
EtOAc/hexane; 88% yield (49.8 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 7.82−7.80 (m, 2H), 7.67 (d, J = 9.5 Hz, 1H), 7.45 (d,
J = 7.0 Hz, 1H), 7.37 (dd, J = 8.0 Hz, J = 6.5 Hz, 2H), 7.19−7.16 (m,
3H), 7.12 (d, J = 6.5 Hz, 3H), 6.60−6.56 (m, 1H), 6.36−6.29 (m,
1H), 4.38 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 136.7, 136.0,
135.0, 132.8, 132.5, 130.9, 130.4, 130.2, 129.8, 128.7, 128.6, 128.2,
126.8, 126.7, 126.4, 126.2, 121.1, 118.96, 118.91, 112.5, 33.5; HRMS
calcd for C20H17N2 [M + H+] 285.1392, found 285.1400.
3-Methyl-1-phenylimidazo[1,5-a]pyridine (4a).10 Eluent, 20%
EtOAc/hexane; 62% yield (26.0 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 7.85 (d, J = 7.0 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H),
7.65 (d, J = 7.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.0 Hz,
1H), 6.73 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.58 (t, J = 7.0 Hz, 1H),
2.68 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 135.0, 134.8, 129.8,
128.6, 126.3, 126.1, 120.9, 118.9, 118.6, 112.5, 12.4.
3-(2-Methylbenzyl)-1-phenylimidazo[1,5-a]pyridine (4f). Eluent,
8% EtOAc/hexane; 99% yield (58.9 mg); semisolid; H NMR (500
1
MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 2H), 7.69 (d, J = 9.5 Hz, 1H),
7.39−7.33 (m, 3H), 7.18 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.0 Hz, 1H),
7.04 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0 Hz,
1H), 6.60 (dd, J = 9.5 Hz, J = 6.5 Hz, 1H), 6.33 (t, J = 6.5 Hz, 1H),
4.32 (s, 2H), 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 136.4,
136.3, 135.0, 134.2, 130.4, 130.2, 128.6, 128.0, 126.8, 126.7, 126.4,
126.2, 121.1, 118.9, 112.5, 31.2, 19.7; HRMS calcd for C21H19N2 [M +
H+] 299.1548, found 299.1545.
3-(tert-Butyl)-1-phenylimidazo[1,5-a]pyridine (4b). Eluent, 5%
EtOAc/hexane; 60% yield (30.0 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 8.05 (d, J = 7.0 Hz, 1H), 7.87−7.86 (m, 2H), 7.78 (d,
J = 9.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 7.0 Hz, 1H), 6.69
(dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.50 (t, J = 6.5 Hz, 1H), 1.59 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 145.0, 135.3, 128.6, 126.6, 126.0,
123.1, 119.2, 118.0, 111.6, 33.4, 28.1; HRMS calcd for C17H19N2 [M +
H+] 251.1548, found 251.1539.
3-(Naphthalen-1-ylmethyl)-1-phenylimidazo[1,5-a]pyridine (4g).
1
Eluent, 5% EtOAc/hexane; 62% yield (41.5 mg); semisolid; H NMR
(500 MHz, CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 7.5 Hz,
2H), 7.87 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.75 (d, J = 8.5
Hz, 1H), 7.58−7.45 (m, 5H), 7.33−7.27 (m, 2H), 7.02 (d, J = 7.0 Hz,
1H), 6.69 (dd, J = 9.5 Hz, J = 6.0 Hz, 1H), 6.39 (t, J = 6.5 Hz, 1H),
4.93 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 136.3, 135.0, 133.8,
131.9, 131.7, 130.3, 128.7, 127.7, 126.9, 126.5, 126.4, 126.2, 125.8,
125.7, 125.4, 123.6, 121.4, 119.0, 118.9, 112.6, 31.1; HRMS calcd for
C24H19N2 [M + H+] 335.1548, found 335.1559.
3-Butyl-1-phenylimidazo[1,5-a]pyridine (4c).17 Eluent, 5%
EtOAc/hexane; 91% yield (46.1 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 7.86−7.84 (m, 2H), 7.74 (d, J = 9.5 Hz, 1H), 7.69 (d,
J = 7.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 6.69 (dd, J = 9.0 Hz, J = 6.5
Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 3.02 (t, J = 7.5 Hz, 2H), 1.85−1.79
(m, 2H), 1.50−1.43 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 138.9, 135.1, 129.8, 128.5, 126.4, 126.2, 126.0, 120.8,
118.9, 118.4, 112.2, 29.2, 26.4, 22.5, 13.7.
3-(Cyclohex-1-en-1-yl)-1-phenylimidazo[1,5-a]pyridine (4h). Elu-
ent, 10% EtOAc/hexane; 87% yield (48.0 mg); semisolid; H NMR
3-Heptyl-1-phenylimidazo[1,5-a]pyridine (4d). Eluent, 5%
EtOAc/hexane; 83% yield (48.8 mg); semisolid; 1H NMR (500
MHz, CDCl3) δ 7.86 (dd, J = 8.5 Hz, J = 0.5 Hz, 2H), 7.75 (d, J = 9.0
Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.26 (dd, J
= 7.5 Hz, J = 7.5 Hz, 1H), 6.70−6.67 (m, 1H), 6.54 (dd, J = 7.5 Hz, J =
7.0 Hz, 1H), 3.02 (t, J = 8.0 Hz, 2H), 1.87 (quin, J = 7.5 Hz, 2H),
1.47−1.41 (m, 2H), 1.38−1.32 (m, 2H), 1.30−1.23 (m, 4H), 0.89 (t, J
= 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 139.0, 135.1, 129.9,
128.6, 126.4, 126.3, 126.0, 120.9, 119.0, 118.5, 112.3, 31.6, 29.4, 28.9,
27.1, 26.7, 22.5, 14.0; HRMS calcd for C20H25N2 [M + H+] 293.2018,
found 293.2021.
1
(500 MHz, CDCl3) δ 8.12 (d, J = 7.0 Hz, 1H), 7.87 (d, J = 7.5 Hz,
2H), 7.74 (d, J = 9.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.26−7.23 (m,
1H), 6.68 (dd, J = 9.0 Hz, J = 6.5 Hz, 1H), 6.49 (t, J = 7.0 Hz, 1H),
6.27−6.25 (m, 1H), 2.64−2.61 (m, 2H), 2.30−2.27 (m, 2H), 1.86−
1.81 (m, 2H), 1.73−1.72 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
139.6, 135.0, 130.6, 129.3, 128.5, 126.9, 126.6, 126.1, 122.6, 119.0,
118.8, 112.3, 27.9, 25.4, 22.5, 21.9; HRMS calcd for C19H19N2 [M +
H+] 275.1548, found 275.1559.
H
DOI: 10.1021/acs.joc.6b01742
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.; Ng,
S.-C.; Rosenberg, S.; Sham, H. L. Bioorg. Med. Chem. Lett. 2002, 12,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01742.
■
S
Copies of NMR spectra for all compounds and HRMS
spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: adimurthy@csmcri.org.
Notes
■
(9) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2007, 46, 4757.
The authors declare no competing financial interest.
(10) Joshi, A.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2016, 18, 464.
(11) (a) Kumar, A.; Kumar, P.; Joshi, C.; Ponnada, S.; Pathak, A. K.;
Ali, A.; Sreedhar, B.; Jain, S. L. Green Chem. 2016, 18, 2514. (b) Qin,
Y.; Zhang, L.; Lv, J.; Luo, S.; Cheng, J. P. Org. Lett. 2015, 17, 1469.
(c) Donthiri, R. R.; Patil, R. D.; Adimurthy, S. Eur. J. Org. Chem. 2012,
2012, 4457. (d) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal. 2011,
353, 1695.
ACKNOWLEDGMENTS
■
CSIR-CSMCRI Communication No. 80/2016. We thank the
“Analytical Discipline and Centralized Instrumental Facilities”
of this institute. A.J. is also thankful to CSIR, New Delhi for his
fellowship. We thank DST, Government of India (EMR/2016/
000010), and CSIR-CSMCRI (OLP-087) for financial support.
(12) Chiassai, L.; Adam, R.; Drechslerova,
B. J. Fluorine Chem. 2014, 164, 44.
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DOI: 10.1021/acs.joc.6b01742
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