Efficient Preparation of Imidazo[1,5- a ]pyridine-1-carboxylic Acids

Article abstract of DOI:10.1055/s-0035-1561489

We report a novel and efficient approach to the synthesis of imidazo[1,5-a]pyridine-1-carboxylic acids. By using the reaction of 2-(aminomethyl)pyridine with acyl chlorides followed by one-pot treatment with trifluoroacetic anhydride, 2,2,2-trifluoro-1-im

Full text of DOI:10.1055/s-0035-1561489

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
D. O. Tverdiy et al.
Paper
Synthesis
Efficient Preparation of Imidazo[1,5-a]pyridine-1-carboxylic Acids
Dmytro O. Tverdiy*a,b,c
O
O
CF3
OH
Maksym O. Chekanova
Pavlo V. Savitskiya
Anatolii R. Syniugina
Sergiy M. Yarmoliuka
Andrey A. Fokinb
1. RCO2Cl
2. TFAA
NaOH
N
N
CH2Cl2, 12 h
N
N
H2O/MeOH
heat
N
R
R
NH2
18 examples
77–96% yield
17 examples
65–96% yield
up to 30 g scale
a Department of Medicinal Chemistry, The Institute of Molecular Biology
and Genetics NAS of Ukraine, 150 Zabolotnogo Str., 03143, Kiev,
Ukraine
R = alkyl, aryl, hetaryl, CF3, CO2Et
chromatography-free
tverdiy_d@ukr.net
b Department of Organic Chemistry, National Technical University of
Ukraine ‘Kiev Polytechnic Institute’, 37 Peremohy Ave., 03056, Kiev,
Ukraine
c Azepine Ltd., Suite 7777, 6 Slington House, Rankine Road, Basingstoke,
RG24 8PH, UK
Received: 30.03.2016
Accepted after revision: 31.05.2016
Published online: 27.07.2016
comparison with those obtained with the reagents men-
tioned above. However, prolonged heating is required for
the reaction with free acid, which may cause destruction of
sensitive groups such as carbamates. Trifluoromethanesul-
fonic anhydride14 does not have this shortcoming because it
acts at low temperature in the presence of base.
DOI: 10.1055/s-0035-1561489; Art ID: ss-2016-t0195-op
Abstract We report a novel and efficient approach to the synthesis of
imidazo[1,5-a]pyridine-1-carboxylic acids. By using the reaction of 2-
(aminomethyl)pyridine with acyl chlorides followed by one-pot treat-
ment with trifluoroacetic anhydride, 2,2,2-trifluoro-1-imidazo[1,5-
a]pyridin-1-ylethanones were obtained, which were then converted
into imidazo[1,5-a]pyridine-1-carboxylic acids in high preparative yields
through haloform cleavage.
RCOCl (1 equiv)
py (4 equiv)
H
N
TFAA (2 equiv)
R
N
NH2
CH2Cl2
N
Key words amides, cyclization, heterocycles, bicyclic compounds,
O
acylation
2b–v
1
Condensed heterocyclic compounds with annelated im-
idazole fragments possess a wide spectrum of biological ac-
tivity. In particular, imidazo[1,2-a]pyridines display antivi-
ral,1 antiulcer,2 and D4-receptor antagonistic activities.3 Im-
idazo[1,5-a]pyridine derivatives were tested for the
treatment of inflammatory4 and cardiovascular5 diseases,
cancer6,7a–c and cognitive impairment of Alzheimer’s dis-
ease.7d Imidazo[1,5-a]pyridine-3-carboxylic acids deriva-
tives4,7b,7d occupy an important place among these com-
pounds. Despite their high biological potential, imid-
azo[1,5-a]pyridines belong to the least studied class of the
imidazopyridines and their preparation is difficult.4,7b,7d
The most common and versatile approach to imid-
azo[1,5-a]pyridines is based on the cyclization of 2-(amino-
methyl)pyridine amides 2 (Scheme 1) through the reaction
with phosphorus oxychloride,4,7,8 polyphosphoric acid,9 and
acetic anhydride in the presence of p-toluenesulfonic acid10
or with acetoformic anhydride.11 The relatively high tem-
peratures required for these processes (80–100 °C) can
cause side reactions that can reduce the yields to 14%,12 es-
pecially for aliphatic acids amides. Alternatively, the use of
propane phosphonic acid anhydride13 gives good results in
O
CF3
N
N
N
N
R
R
3b–s
4b–s
Scheme 1 One-pot synthesis of 2,2,2-trifluoro-1-(imidazo[1,5-a]pyri-
din-1-yl)ethanones 4 from 2-(aminomethyl)pyridine (1)
We have found that the reaction of trifluoroacetic anhy-
dride (TFAA) with 2 in the presence of pyridine results in
the formation of the imidazolium ring at low temperatures
(–50 to –10 °C), while at the same time tryfluoroacetylation
of the imidazolium ring takes place. This fact may be used
for a one-pot production of trifluoro-1-(imidazo[1,5-a]pyr-
idin-1-yl)ethanones, which are precursors of imidazo[1,5-
a]pyridine-1-carboxylic acids.
We first optimized the reaction conditions for the cy-
clization of N-(pyridin-2-ylmethyl)acetamide (2b) to 3-
methyl imidazo[1,5-a]pyridine (3b) (Scheme 1,R = Me). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
D. O. Tverdiy et al.
Paper
Synthesis
addition of equimolar amounts of TFAA in dichloromethane
to a solution of 2b in dichloromethane at room temperature
gave a mixture of 3b and its trifluoroacetic derivative 4b to-
gether with starting compound (Table 1, entries 1 and 2).
A temperature decrease to –10 °C changed the ratio of
the products only slightly (Table 1, entries 3 and 4). Addi-
tion of two equivalents of TFAA without a base increased
the conversion of the starting compound, although the re-
action was incomplete (entries 2 and 4). With the addition
of triethylamine, almost pure 2,2,2-trifluoro-1-(3-meth-
ylimidazo[1,5-a]pyridin-1-yl)ethanone (4b) was obtained
(entries 5–8). Thus, trifluoroacetic acid, which is produced
in the reaction (Scheme 1), needs to be trapped by triethyl-
amine to complete the acylation of the imidazopyridine
ring. However, this is accompanied by the reaction between
triethylamine and TFAA.15 The replacement of triethyl-
amine by pyridine increased the yields (entries 10 and 11),
allowing the reaction to be carries out at –10 °C. These con-
ditions were chosen to be standard for all further transfor-
mations.
Table 2 Yields of 2,2,2-Trifluoro-1-imidazo[1,5-a]pyridin-1-ylethan-
ones 4a–sa
Entry
R
Product
Temp. (°C)
Yield (%)
1
2
H
4ab
4b
4c
4d
4e
4f
–10
–10
–10
–10
–50
–50
–10
–50
–50
–50
–50
–10
–50
–50
–50
–50
–10
–10
36
90
92
95
83
81
89
77
79
81
83
95
84
83
85
80
96
95
Me
3
Et
4
n-Pr
5
i-Pr
6
c-Pr
7
i-Bu
4g
4h
4i
8
t-Bu
9
c-Bu
c-Pent
c-Hex
PhCH2CH2
Ph
10
11
12
13
14
15
16
17
18
4j
4k
4l
4m
4n
4o
4p
4q
4s
3-Py
4-Py
4-(2-Cl-Py)-
CF3
Table 1 Yields of the Cyclodehydration–Acylation Reaction of 2b
Entry
Base
Temp
(°C)
TFAA
(equiv) (%)
Conv.
Yield of 3b Yield of 4b
(%) (%)
EtO2C
1
2
–
–
–
–
20
20
1
2
1
2
1
2
1
2
1
2
2
42
24
18
a Reaction time was 12 h for all entries.
b Formed together with 2,2,2-trifluoro-3-imidazo[1,5-a]pyridin-1-ylethan-
one (4a′).
50
51
–
50
23
59
25
60
28
70
29
80
90
3
–10
–10
20
28
–
4
59
5
Et3N
56
31
8
tures of the target compounds 4e, 4f, 4h–k, and 4m–p to-
gether with up to 30% of 2,2,2-trifluoro-1-[3-(trifluoro-
methyl)imidazo[1,5-a]pyridine-1-yl]-ethanone (4q), the
formation of which can be explained by a reamidation reac-
tion. The formation of byproducts was reduced to 7–15% by
carrying out the reaction at –50 °C.
We then studied the reactivity of N-(pyridin-2-ylmeth-
yl)formamide (2a; Scheme 2). The reaction with TFAA in
the presence of pyridine resulted in a mixture of 2,2,2-tri-
fluoro-1-imidazo[1,5-a]pyridin-1-ylethanone (4a) and
2,2,2-trifluoro-1-imidazo[1,5-a]pyridin-3-ylethanone (4a′)
(Table 2 and Scheme 2) in 2:3 ratio according to the NMR
spectroscopic analysis.
We applied the same reaction conditions to 2-(amino-
methyl)pyridine amides with strong carboxylic acids such
as trifluoroacetic, trichloroacetic, and ethyloxalic acids (2q–
s; Scheme 1 and Table 2) that could potentially form an im-
idazo[1,5-a]pyridinium ring with electron-withdrawing
groups in the 3-position. The reaction of 1 with three
equivalents of TFAA and four equivalents of pyridine gave
trifluoroacetamide 2q, followed by cyclization to 3q and
acylation to 2,2,2-trifluoro-1-[3-(trifluoromethyl)imid-
azo[1,5-a]pyridin-1-yl]ethanone (4q; Scheme 1 and Table
2). The reaction of 2q with one equivalent of TFAA at –15 to
–10 °C provided a mixture of 2q/3q/4q in a 1:2:1 ratio and
6
Et3N
20
68
7
Et3N
–10
–10
20
62
34
10
37
–
8
Et3N
80
9
pyridine
pyridine
pyridine
66
10
11
20
100
100
–10
–
We also found that TFAA can be added directly to the
mixture of reactants without isolation of intermediates,
which requires four equivalents of base to complete the re-
action. This allows all three steps to be combined in a one-
pot, three-step preparation of 2,2,2-trifluoro-1-imid-
azo[1,5-a]pyridin-1-ylethanones 4a–s containing a range of
functional groups (Table 2).
The above reaction conditions were applied to the
preparation of 2b and amides 2c–p (Table 2). Linear aliphat-
ic amides 2b–d, 2g, and 2l formed 2,2,2-trifluoro-1-imid-
azo[1,5-a]pyridin-1-ylethanones 4b–d, 4g, and 4l as pure
products with high yields (86–95%; Table 2, entries 2–4, 7
and 12). Under the same conditions, other aliphatic (entries
5, 6, 8–11) and aromatic (entries 13–16) amides gave mix-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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D. O. Tverdiy et al.
Paper
Synthesis
Methyl N-(pyridin-2-ylmethyl)carbamate (2t; R = MeO)
was transformed into 4q under standard cyclization condi-
tions. N′,N′-Diethyl-N-(2-pyridylmethyl)urea (2u; R = Et2N)
was inert towards cyclization upon treatment with TFAA.
The 2,2,2-trifluoro-1-imidazo[1,5-a]pyridin-1-ylethan-
ones 4b–s were transformed into the corresponding car-
boxylic acids 5b–s by haloform cleavage in high yields
(Scheme 4 and Table 3). The reaction of 4s was accompa-
nied by hydrolysis of the ester group.
TFAA (2 equiv)
py (3 equiv)
H
N
O
N
N
CH2Cl2
N
2a
3a
O
CF3
O
O
+
CF3
N
OH
N
N
N
1. NaOH, aq MeOH,
reflux
N
N
CF3
2. H+
N
N
O
4a
40%
4a'
60%
R
R
4b–s
5b–s
Scheme 2 Cyclization of the 2a and acylation of the ring with TFAA
Scheme 4 Haloform cleavage of 2,2,2-trifluoro-1-(imidazo[1,5-a]pyri-
din-1-yl)ethanones 4b–s
at –50 °C afforded 3-trifluoromethylimidazo[1,5-a]pyridine
(3q) as a single product (Scheme 1). Trichloroacetamide 2r
with two equivalents of TFAA gave 4q also as a sole product
(Scheme 3). When ethyloxalic amide 2s was treated with
one equivalent of TFAA at –10 °C only non-acylated imid-
azo[1,5-a]pyridine 3s was obtained (Scheme 1, R = CO2Et).
The acylation only took place with more than one equiva-
lent of TFAA; with two equivalents of TFAA at room tem-
perature the reaction was complete. Therefore, the rates of
the acylation of the imidazo[1,5-a]pyridinium ring of ethyl
imidazo[1,5-a]pyridine-3-carboxylate (3s) with TFAA is sig-
nificantly lower than the cyclization rates of the starting
amide in comparison with other aliphatic and aromatic
amides. In the case of amides 2b–p, the formation of a mix-
ture of starting amide, non-acylated imidazo[1,5-a]pyri-
dine 3b–p, and product 4b–p was observed with one equiv-
alent of TFAA even at –50 °C.
Table 3 Preparation of Imidazo[1,5-a]pyridine-1-carboxylic Acids
through Haloform Cleavagea
Entry
R
Product
Yield (%)
1
2
Me
5b
5c
5d
5e
5f
65
72
80
77
75
85
77
79
81
83
95
84
83
85
80
96
80
Et
3
n-Pr
4
i-Pr
5
c-Pr
6
i-Bu
5g
5h
5i
7
t-Bu
8
c-Bu
9
c-Pent
c-Hex
PhCH2CH2
Ph
5j
10
11
12
13
14
15
16
17
5k
5l
TFAA
(2 equiv)
CCl3COCl (1 equiv)
py ( 4 equiv)
5m
5n
5o
5p
5q
5sb
H
CCl3
N
3-Py
4-Py
4-(2-Cl-Py)
CF3
NH2
CH2Cl2
N
N
O
1
2s
O
HO2C
CF3
a Reaction time was 1 h for all entries.
b Ethyl (1-trifluoroacetyl)imidazo[1,5-a]pyridine-3-carboxylate 4s (R =
N
N
N
CO2Et) was used as a starting compound.
N
CF3
CF3
3r
4q
In conclusion, a convenient, one-pot method for the
synthesis of 2,2,2-trifluoro-1-imidazo[1,5-a]pyridin-1-
ylethanones and some imidazo[1,5-a]pyridines from 2-
(aminomethyl)pyridine was developed. Trifluoroacetic an-
hydride was used for the cyclization of 2-(aminometh-
Scheme 3 Reaction of the 2,2,2-trichloro-N-(pyridin-2-ylmethyl)acet-
amide (2r), obtained in situ from 1, with TFAA
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
D. O. Tverdiy et al.
Paper
Synthesis
yl)pyridine amides followed by imidazolium ring acylation.
The obtained trifluoroacetyl derivatives gave imidazo[1,5-
a]pyridine-1-carboxylic acids by haloform cleavage in high
preparative yields.
2,2,2-Trifluoro-1-(3-propylimidazo[1,5-a]pyridin-1-yl)ethanone
(4d)
Yield: 3.38 g (95%); beige solid; mp 98–100 °C.
1H NMR (DMSO-d6): δ = 1.00 (t, J = 6.7 Hz, 3 Н), 1.77–1.82 (m, 2 H),
3.05 (t, J = 6.5 Hz, 2 H), 7.25 (t, J = 6.6 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H),
8.21 (d, J = 8.8 Hz, 1 H), 8.68 (d, J = 6.6 Hz, 1 H).
1
13C NMR (DMSO-d6): δ = 13.5, 19.5, 27.4, 116.2, 117.2 (q, JC–F
=
=
Starting materials and solvents were purchased from commercial
2
1
291.4 Hz), 118.4, 121.8, 125.3, 130.3, 138.4, 142.4, 171.5 (q, JC–F
suppliers and were used without further purification. H NMR spec-
tra were recorded with a Varian VXR 400 instrument at 400 MHz. 13
C
33.3 Hz).
MS: m/z (%) = 258 (12) [M + 2]+, 257 (100) [M + 1]+, 187 (4) [M – CF3]+.
NMR spectra were recorded with a Varian VXR 400 instrument at 100
MHz. Chemical shifts are reported as parts per million (δ) downfield
from an internal standard of tetramethylsilane, and spin multiplici-
ties are given as s (singlet), d (doublet), dd (double doublet), t (trip-
let), q (quartet), or m (multiplet). HPLC-MS analysis was performed
with an Agilent 1100 LC/MSD SL separations module and Mass Quad
G1956B mass detector with electrospray ionization (+ve or –ve ion
mode as indicated) and with HPLC performed using Zorbax SB-C18,
Rapid Resolution HT Cartridge 4.6 × 30 mm 1.8-Micron (Agilent
P/N:823975–902) i.d. column, at a temperature of 40 °C with gradient
elution of 0–100% MeCN (with 1 mL/L HCO2H): H2O (with 1 mL/L
HCO2H) at a flow rate of 3 mL/min and a run time of 2.8 min. Com-
pounds were detected at 215 nm with a Diode Array G1315B detec-
tor.
2,2,2-Trifluoro-1-[3-(2-methylpropyl)imidazo[1,5-a]pyridin-1-
yl]ethanone (4g)
Yield: 3.34 g (89%); yellow solid; mp 118 °C.
1H NMR (DMSO-d6): δ = 0.96 (d, J = 6.3 Hz, 6 H), 2.12–2.23 (m, 1 H),
2.98 (d, J = 7.0 Hz, 2 H), 7.25 (t, J = 6.6 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H),
8.23 (d, J = 8.8 Hz, 1 H), 8.73 (d, J = 6.6 Hz, 1 H).
1
13C NMR (DMSO-d6): δ = 22.1, 26.7, 34.0, 116.3, 117.2 (q, JC–F
291.4 Hz), 121.9, 125.4, 130.2, 138.3, 141.8, 171.6 (q, 2JC–F = 33.3 Hz).
=
MS: m/z (%) = 272 (18) [M + 2]+, 271 (100) [M + 1]+, 201 (2) [M – CF3]+.
2,2,2-Trifluoro-1-[3-(2-phenylethyl)imidazo[1,5-a]pyridin-1-
yl]ethanone(4l)
2,2,2-Trifluoro-1-imidazo[1,5-a]pyridin-1ylethanones 4b–d, 4g, 4l,
with α-Unbranched Aliphatic Substituents, from 2-Aminometh-
ylpyridine in One Pot; General Procedure
Yield: 4.19 g (95%); off-white powder; mp 99–101 °C.
1H NMR (DMSO-d6): δ = 3.14 (t, J = 7.2 Hz, 2 Н), 3.38 (t, J = 7.2 Hz, 2 Н),
7.13–7.29 (m, 4 H), 7.29–7.35 (m, 2 H), 7.63 (t, J = 7.6 Hz, 1 H), 8.23 (d,
J = 8.8 Hz, 1 H), 8.65 (d, J = 6.6 Hz, 1 H).
2-Aminomethylpyridine (1.5 g, 13.9 mmol) and pyridine (4.72 g, 59.6
mmol) were dissolved in CH2Cl2 (20 mL) and the solution was cooled
by using an ice bath. A solution of acyl chloride (14.3 mmol) in CH2Cl2
(10 mL) was added dropwise at 0 to –5 °C. After the addition, the mix-
ture was stirred for 15 min, then a solution of TFAA (6.41 g,
30.5 mmol) in CH2Cl2 (10 mL) was added dropwise at –15 to –10 °C
(ice-salt bath). The reaction mixture was allowed to stand overnight
in the bath, then it was washed with sat. aq NaHCO3, dried (Na2SO4)
and evaporated, or it was first evaporated and then washed with sat.
NaHCO3 and filtered.
13C NMR (DMSO-d6): δ = 27.5, 31.9, 113.42, 116.2, 117.2 (q, JC–F
=
1
291.4 Hz), 118.3, 121.8, 125.27, 126.1, 128.2, 128.6, 130.3, 138.4,
140.6, 141.8, 171.6 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 320 (19) [M + 2]+, 319 (100) [M + 1]+.
Synthesis of 2,2,2-Trifluoro-1-(3-alkyl(aryl)imidazo[1,5-a]-pyri-
dine-1-yl)ethanones 4e, 4f, 4h–k, 4m, with Aromatic and
α-Branched Aliphatic Substituents, from 2-Aminomethylpyridine
in One Pot; General Procedure
2,2,2-Trifluoro-1-(3-methylimidazo[1,5-a]pyridin-1-yl)ethanone
2-(Aminomethyl)pyridine (1.5 g, 13.9 mmol) and pyridine (4.72 g,
59.6 mmol) were dissolved in CH2Cl2 (20 mL), and the solution was
cooled by using an ice bath. A solution of acyl chloride (14.3 mmol) in
CH2Cl2 (10 mL) was added dropwise at 0 to 5 °C. After the addition,
the mixture was stirred for 15 min, then placed in an acetone-dry ice
bath and a solution of TFAA (6.41 g, 30.5 mmol) in CH2Cl2 (10 mL) was
added dropwise at –50 to –40 °C. The mixture was stirred at this tem-
perature for 2 h, then stirred overnight. The reaction solution was
washed with sat. aq NaHCO3, the CH2Cl2 layer was dried over Na2SO4
and evaporated. The product was purified by crystallization from
methanol.
(4b)
Yield: 2.85 g (90%); beige solid; mp 177 °C.
1H NMR (DMSO-d6): δ = 2.7 (s, 3 Н), 7.26 (t, J = 6.6 Hz, 1 H), 7.64 (t, J =
7.6 Hz, 1 H), 8.20 (d, J = 8.8 Hz, 1 H), 8.59 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 12.3, 116.1, 117.2 (q, 1JC–F = 291.4 Hz), 118.2,
121.6, 125.4, 130.2, 138.3, 139.2, 171.4 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 230 (8) [M + 2]+, 229 (100) [M + 1]+, 159 (10) [M – CF3]+.
2,2,2-Trifluoro-1-(3-ethylimidazo[1,5-a]pyridin-1-yl)ethanone
(4c)
Yield: 3.09 g (92%); yellow solid; mp 149–150 °C.
2,2,2-Trifluoro-1-[3-(1-methylethyl)imidazo[1,5-a]pyridin-1-
yl]ethanone (4e)
1H NMR (DMSO-d6): δ = 1.35 (t, J = 7.4 Hz, 3 H), 3.08 (q, J = 7.4 Hz,
2 H), 7.26 (t, J = 6.6 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 8.23 (d, J = 8.8 Hz,
1 Н), 8.66 (d, J = 6.6 Hz, 1 Н).
13C NMR (DMSO-d6): δ = 10.5, 19.1, 116.2, 117.2 (q, JC–F = 291.4 Hz),
118.4, 121.7, 125.2, 130.3, 138.5, 143.5, 171.5 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 244 (12) [M + 2]+, 243 (100) [M + 1]+, 173 (7) [M – CF3]+.
Yield: 2.95 g (83%); beige solid; mp 113 °C.
1H NMR (DMSO-d6): δ = 1.36 (d, J = 6.2 Hz, 6 Н), 3.54–3.63 (m, J =
6.2 Hz, 1 H), 7.26 (t, J = 6.6 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 8.25 (d, J =
8.8 Hz, 1 H), 8.74 (d, J = 6.6 Hz, 1 H).
1
1
13C NMR (DMSO-d6): δ = 6.2, 6.8, 115.8, 117.2 (q, JC–F = 291.4 Hz),
118.6, 121.7, 125.3, 130.4, 138.6, 146.9, 171.5 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 258 (13) [M + 2]+, 257 (100) [M + 1]+, 187 (7) [M – CF3]+.
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D. O. Tverdiy et al.
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Synthesis
1-(3-Cyclopropylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroeth-
2,2,2-Trifluoro-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)ethanone
anone (4f)
(4m)
Yield: 2.86 g (81%); orange solid; mp 132–133 °C.
Yield: 3.38 g (84%); yellow solid; mp 143 °C.
1H NMR (DMSO-d6): δ = 0.97–1.03 (m, 2 Н), 1.08–1.16 (m, 2 H), 2.42–
2.52 (m, 1 H), 7.26 (t, J = 6.6 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 8.17 (d,
J = 8.8 Hz, 1 H), 8.79 (d, J = 6.6 Hz, 1 H).
1H NMR (DMSO-d6): δ = 7.27 (t, J = 6.6 Hz, 1 H), 7.57–7.67 (m, 3 H),
7.71 (t, J = 7.6 Hz, 1 H), 7.87 (d, J = 4.8 Hz, 2 H), 8.34 (d, J = 8.8 Hz, 1 H),
8.76 (d, J = 6.6 Hz, 1 H).
1
1
13C NMR (DMSO-d6): δ = 6.2, 6.8, 116.3, 117.2 (q, JC–F = 291.4 Hz),
13C NMR (DMSO-d6): δ = 117.2, 117.2 (q, JC–F = 291.4 Hz), 118.6,
118.4, 121.3, 125.0, 130.4, 138.6, 143.5, 171.4 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 256 (17) [M + 2]+, 255 (100) [M + 1]+, 185 (7) [M – CF3]+.
123.0, 125.6, 128.0, 128.9, 129.2, 130.1, 131.0, 139.0, 140.5, 172.1 (q,
2JC–F = 33.3 Hz).
MS: m/z (%) = 292 (17) [M + 2]+, 291 (100) [M + 1]+, 121 (1) [M – CF3]+.
1-(3-tert-Butylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroeth-
anone (4h)
2,2,2-Trifluoro-1-(imidazo[1,5-a]pyridyl)ethanones 4a and 4a′
Yield: 2.89 g (77%); yellow solid; mp 157–158 °C.
1H NMR (DMSO-d6): δ = 1.52 (s, 1 H), 7.21 (t, J = 6.6 Hz, 1 H), 7.64 (t,
J = 7.6 Hz, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.94 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 18.1, 25.8, 30.4, 116.3, 117.2 (q, JC–F
291.4 Hz), 118.5, 121.7, 125.2, 130.4, 138.6, 144.9, 171.6 (q, JC–F
33.3 Hz).
MS: m/z (%) = 272 (14) [M + 2]+, 271 (100) [M + 1]+.
N-(2-Pyridylmethyl)formamide16 (1.5 g, 11 mmol) and pyridine (2.88
g, 36.4 mmol) were dissolved in CH2Cl2 (20 mL), and the solution was
cooled by using an ice-salt bath. A solution of TFAA (5.09 g, 24.2
mmol) in CH2Cl2 (10 mL) was added dropwise at –15 to –10 °C. The
reaction mixture was allowed to stand overnight in the bath, then the
solvent was evaporated and the residue was treated with sat. aq
NaHCO3, filtered, and washed with water. After drying, the mixture of
the isomers was separated by column chromatography (SiO2, CH2Cl2).
1
=
=
2
The synthesis of compounds 4a and 4a′ was reported by Khodakovs-
kiy,17 but compound 4a was not isolated.
1-(3-Cyclobutylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroeth-
anone (4i)
Yield: 2.94 g (79%); pale yellow solid; mp 126–128 °C.
2,2,2-Trifluoro-1-(imidazo[1,5-a]pyridin-1-yl)ethanone (4a)
1H NMR (DMSO-d6): δ = 1.89–2.00 (m, 1 H), 2.05–2.17 (m, 1 H), 2.36–
2.48 (m, 4 H), 4.00–4.12 (m, 1 H), 7.22 (t, J = 6.6 Hz, 1 H), 7.62 (t, J =
7.6 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 8.48 (d, J = 6.6 Hz, 1 H).
1
Yield: 2.85 g (90%); yellow solid; mp 219–220 °C.
1H NMR (DMSO-d6): δ = 7.14 (t, J = 6.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H),
8.26 (d, J = 8.8 Hz, 1 H), 8.59 (s, 1 Н), 8.76 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 18.1, 25.8, 30.4, 116.3, 117.2 (q, JC–F
=
=
1
13C NMR (DMSO-d6): δ = 117.1 (q, JC–F = 291.4 Hz), 116.5, 118.2,
2
291.4 Hz), 118.5, 121.7, 125.2, 130.4, 138.6, 144.9, 171.6 (q, JC–F
122.8, 126.6, 130.9, 131.9, 137.6, 172.0 (q, 2JC–F = 33.3 Hz).
19F NMR (pyridine-d5): δ = –72.21.
33.3 Hz).
MS: m/z (%) = 270 (15) [M + 2]+, 269 (100) [M + 1]+, 242 (2) [M + 2 –
CO]+, 241 (15) [M + 1 – CO]+, 171 (9) [M + 2 – CO – CF3]+.
2,2,2-Trifluoro-1-(imidazo[1,5-a]pyridin-3-yl)ethanone (4a′)
Yield: 2.85 g (90%); yellow solid; mp 143–144 °C (Lit.17 142–143).
1H NMR (DMSO-d6): δ = 7.41 (t, J = 6.6 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H),
7.96 (s, 1 Н), 8.09 (d, J = 8.8 Hz, 1 H), 9.59 (d, J = 6.6 Hz, 1 H).
1-(3-Cyclopentylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroeth-
anone (4j)
Yield: 3.17 g (81%); yellow solid; mp 101 °C.
1H NMR (DMSO-d6): δ = 1.60–1.72 (m, 2 H), 1.72–1.83 (m, 2 H), 1.83–
1.98 (m, 2 H), 2.06–2.21 (m, 2 H), 3.60–3.71 (m, 1 H), 7.23 (t, J =
1
13C NMR (DMSO-d6): δ = 116.6, 117.1 (q, JC–F = 292.4 Hz), 118.2,
118.6, 122.8, 126.6, 130.9, 131.9, 137.7, 172.0 (q, 2JC–F = 33.3 Hz).
6.6 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 8.68 (d, J =
6.6 Hz, 1 H).
2,2,2-Trifluoro-1-(3-pyridylimidazo[1,5-a]pyridin-1-yl)ethanones
4n–p; General Procedure
1
13C NMR (DMSO-d6): δ = 25.1, 30.2, 35.4, 116.2, 117.2 (q, JC–F
=
=
2
2-Aminomethylpyridine (1.5 g, 13.9 mmol) and pyridine (4.72 g, 59.6
mmol) were dissolved in CH2Cl2 (20 mL), and the solution was cooled
by using an ice bath. The hydrochloride of pyridine-carboxylic acid
chloride (14.3 mmol) was added portionwise at 0 to 5 °C to the reac-
tion mixture (for 4p a solution of acyl chloride in CH2Cl2 was added).
After the addition, the mixture was stirred for 15 min, then a solution
of trifluoroacetic anhydride (6.41 g, 30.5 mmol) in CH2Cl2 (10 mL)
was added dropwise at –15 to –10 °C (ice-salt bath). The mixture was
allowed to stand overnight in the bath, then washed with sat. aq
NaHCO3, dried over Na2SO4, and evaporated, or it was first evaporated,
then washed with sat. aq NaHCO3 and filtered.
291.4 Hz), 118.4, 121.5, 125.2, 130.2, 138.7, 145.7, 171.5 (q, JC–F
33.3 Hz).
MS: m/z (%) = 284 (17) [M + 2]+, 283 (100) [M + 1]+, 213 (2) [M – CF3]+.
1-(3-Cyclohexylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroeth-
anone (4k)
Yield: 3.41 g (83%); yellow solid; mp 117 °C.
1H NMR (DMSO-d6): δ = 1.20–1.35 (m, 1 H), 1.37–1.51 (m, 2 H), 1.51–
1.64 (m, 2 H), 1.64–1.74 (m, 1 H), 1.74–1.87 (m, 2 H), 1.87–2.02 (m,
2 H), 3.20–3.32 (m, 1 H), 7.23 (t, J = 6.6 Hz, 1 H), 7.62 (t, J = 7.6 Hz,
1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8.75 (d, J = 6.6 Hz, 1 H).
1
2,2,2-Trifluoro-1-(3-pyridin-3-ylimidazo[1,5-a]pyridin-1-yl)eth-
anone (4n)
13C NMR (DMSO-d6): δ = 25.2, 25.4, 30.1, 34.0, 116.2, 117.2 (q, JC–F
=
=
2
291.4 Hz), 118.5, 121.8, 125.3, 130.2, 138.4, 146.1, 171.6 (q, JC–F
Yield: 3.35 g (83%); pale beige solid; mp 185 °C.
33.3 Hz).
MS: m/z (%) = 298 (23) [M + 2]+, 297 (100) [M + 1]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
D. O. Tverdiy et al.
Paper
Synthesis
1H NMR (DMSO-d6): δ = 7.28 (t, J = 6.6 Hz, 1 H), 7.65 (t, J = 5.6 Hz, 1 H),
7.72 (t, J = 7.6 Hz, 1 H), 8.32 (d, J = 7.4 Hz, 1 H), 8.36 (d, J = 8.8 Hz, 1 H),
8.79 (d, J = 3.7 Hz, 1 H), 8.83 (d, J = 6.6 Hz, 1 H), 9.05 (s, 1 H).
1H NMR (DMSO-d6): δ = 7.48 (t, J = 6.4 Hz, 1 H), 7.85 (t, J = 7.6 Hz, 1 H),
7.38 (d, J = 8.8 Hz, 1 H), 8.81 (d, J = 6.2 Hz, 1 H).
1
1
13C NMR (DMSO-d6): δ = 116.5 (q, JC–F = 290.9 Hz), 118.5 (q, JC–F
=
1
2
13C NMR (DMSO-d6): δ = 117.1 (q, JC–F = 291.4 Hz), 117.3, 118.5,
269.5 Hz), 118.8, 118.9, 122.4, 125.4, 126.9 (q, JC–F = 40.1 Hz), 132.0,
123.2, 124, 124.4, 125.8, 136.5, 138.0, 139.0, 149.3, 150.6, 171.6 (q,
139.0, 172.7 (q, 2JC–F = 34.0 Hz).
2JC–F = 33.3 Hz).
19F NMR (DMSO-d6): δ = –62.83, –72.25.
MS: m/z (%) = 284 (11) [M + 2]+, 283 (100) [M + 1]+.
MS: m/z (%) = 293 (15) [M + 2]+, 292 (100) [M + 1]+.
2,2,2-Trifluoro-1-(3-pyridin-4-ylimidazo[1,5-a]pyridin-1-yl)eth-
anone (4o)
Ethyl Imidazo[1,5-a]pyridine-3-carboxylate (3s)
2-(Aminomethyl)pyridine (1.5 g, 13.9 mmol) and pyridine (3.62 g,
45.8 mmol) were dissolved in CH2Cl2 (20 mL), and the solution was
cooled by using an ice bath. A solution of ethyl oxalyl chloride (1.89
g, 13.9 mmol) in CH2Cl2 (10 mL) was added dropwise at 0 to –5 °C. Af-
ter addition, the mixture was stirred for 2 h and a solution of TFAA
(3.06 g, 14.6 mmol) in CH2Cl2 (10 mL) was added dropwise at –15 to
–10 °C (ice-salt bath). The reaction mixture was allowed to stand
overnight in the bath, then washed with sat. aq NaHCO3, and the
CH2Cl2 layer was dried over Na2SO4 and concentrated.
Yield: 3.43 g (85%); yellow solid; mp 183 °C.
1H NMR (DMSO-d6): δ = 7.33 (t, J = 6.6 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H),
7.90 (d, J = 2.8 Hz, 2 H), 8.35 (d, J = 8.8 Hz, 1 H), 8.81 (d, J = 2.8 Hz,
2 H), 8.93 (d, J = 6.6 Hz, 1 H).
1
13C NMR (DMSO-d6): δ = 117.0 (q, JC–F = 291.4 Hz), 117.5, 118.6,
2
122.4, 123.5, 125.8, 131.0, 135.3, 137.7, 139.1, 150.4, 172.3 (q, JC–F
33.3 Hz).
MS: m/z (%) = 293 (15) [M + 2]+, 292 (100) [M + 1]+.
=
Yield: 2.4 g (91%); white solid; mp 80 °C (Lit.13 80 °C).
The 1H and 13C NMR spectroscopic data were identical to those re-
ported previously.4,14,18
1-[3-(2-Chloropyridin-4-yl)imidazo[1,5-a]pyridin-1-yl]-2,2,2-tri-
fluoroethanone (4p)
Yield: 3.62 g (80%); yellow solid; mp 257–258 °C.
Ethyl (1-Trifluoroacetyl)imidazo[1,5-a]pyridine-3-carboxylate
(4s)
1H NMR (DMSO-d6): δ = 7.34 (t, J = 6.6 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H),
7.91 (d, J = 3.1 Hz, 1 H), 7.96 (s, 1 H), 8.33 (d, J = 8.8 Hz, 1 H), 8.63 (d,
J = 3.1 Hz, 1 H), 8.95 (d, J = 6.6 Hz, 1 H).
2-(Aminomethyl)pyridine (1.5 g, 13.9 mmol) and pyridine (5.55 g,
59.6 mmol) were dissolved in MeCN (30 mL), and the solution was
cooled by using an ice bath. A solution of ethyl oxalyl chloride (1.89
g, 13.9 mmol) in MeCN (10 mL) was added dropwise at 0 to –5 °C. Af-
ter the addition, the mixture was stirred for 2 h and a solution of
TFAA (6.41 g, 30.5 mmol) in MeCN (15 mL) was added dropwise at
–15 to –10 °C (ice-salt bath). The reaction mixture was allowed to
stand overnight in the bath, then the mixture was poured in sat. aq
sodium hydrocarbonate, filtered, and washed with water.
1
13C NMR (DMSO-d6): δ = 116.9 (q, JC–F = 291.4 Hz), 117.7, 118.4,
118.6, 122.0, 122.7, 123.5, 126.2, 131.5, 136.6, 138.8, 139.2, 150.8,
151.1, 172.0 (q, 2JC–F = 33.3 Hz).
MS: m/z (%) = 327 (5) [M + 3]+, 326 (31) [M + 2]+, 327 (16) [M + 1]+,
326 (100) [M]+.
3-(Trifluoromethyl)imidazo[1,5-a]pyridine (3q)
2-(Aminomethyl)pyridine (1.5 g, 13.9 mmol) and pyridine (4.72 g,
59.6 mmol) were dissolved in CH2Cl2 (35 mL), and the solution was
cooled to –50 °C. A solution of TFAA (3.00 g, 14.3 mmol) in CH2Cl2 (15
mL) was added dropwise at –10 to –5 °C, then a solution of trifluoro-
acetic anhydride (3.12 g, 14.9 mmol) in CH2Cl2 (15 mL) was added
dropwise at –50 to –55 °C. The reaction mixture was allowed to stand
at the same temperature for 1 h, then washed with sat. aq NaHCO3,
dried over Na2SO4, and evaporated.
Yield: 3.77 g (95%); yellow solid; mp 225 °C.
1H NMR (DMSO-d6): δ = 1.40 (t, J = 6.6 Hz, 3 Н), 4.48 (q, J = 6.6 Hz,
2 H), 7.51 (t, J = 6.6 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 8.40 (d, J = 8.8 Hz,
1 H), 9.45 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 14.2, 61.7, 116.6 (q, JC–F = 290.7 Hz), 118.5,
118.6, 123.1, 128.0, 129.1, 132.2, 139.0, 158.4, 172.9 (q, JC–F
1
2
=
33.9 Hz).
MS: m/z (%) = 288 (14) [M + 2]+, 287 (100) [M + 1]+, 259 (3) [M + 2 –
Yield: 2.43 g (94%); pale yellow liquid.
1H NMR (DMSO-d6): δ = 7.00 (t, J = 6.6 Hz, 1 H), 7.10 (t, J = 7.6 Hz, 1 H),
7.63 (s, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 8.39 (d, J = 6.6 Hz, 1 H).
CO]+, 242 (3) [M + 2 – C2H5OH]+, 241 (23) [M + 1 – C2H5OH]+.
3-Alkylimidazo[1,5-a]pyridine-1-carboxylic acids 5b–f; General
Procedure
1
13C NMR (DMSO-d6): δ = 115.6, 118.5, 119.8 (q, JC–F = 267.6 Hz),
120.4, 121.8, 122.2 (q, 3JC–F = 2.1 Hz), 124.1 (q, 2JC–F = 40.1 Hz), 132.9.
19F NMR (DMSO-d6): δ = –62.07.
1-(3-Alkylimidazo[1,5-a]pyridine-1-yl)-2,2,2-trifluoroethanone 4b–f
(6 mmol) was dissolved in MeOH (20 mL), and a solution of NaOH (1.2
g, 30 mmol) in water (20 mL) was added. The mixture was heated at
reflux for 1 h and, after cooling, MeOH was evaporated. HCl (3%) was
added dropwise to the aqueous solution under cooling and stirring to
obtain pH 5.3, then the solution was evaporated to dryness. The mix-
ture was heated to reflux in 15% solution of CH2Cl2 in MeOH and fil-
tered. The filter cake was washed with the hot solution mentioned
above. The solvent was evaporated to give the desired product.
2,2,2-Trifluoro-1-[3-(trifluoromethyl)imidazo[1,5-a]pyridin-1-
yl]ethanone (4q)
2-(Aminomethyl)pyridine (1.5 g, 13.9 mmol) and pyridine (4.72 g,
59.6 mmol) were dissolved in CH2Cl2 (20 mL), and the solution was
cooled by using ice-salt bath. A solution of trifluoroacetic anhydride
(9.32 g, 44.4 mmol) in CH2Cl2 (10 mL) was added dropwise at –15 to
–10 °C and the mixture was allowed to stand overnight in the bath.
The solvent was evaporated and the residue was treated with sat. aq
NaHCO3, filtered, and washed with water.
3-Methylimidazo[1,5-a]pyridine-1-carboxylic Acid (5b)
Yield: 0.69 g (65%); beige solid; mp 223–224 °C.
Yield: 3.75 g (96%); white solid; mp 125 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
D. O. Tverdiy et al.
Paper
Synthesis
1H NMR (DMSO-d6): δ = 2.63 (s, 1 H), 6.92 (t, J = 6.6 Hz, 1 H), 7.19 (t,
J = 7.6 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 8.29 (d, J = 6.6 Hz, 1 H).
3-Alkyl(aryl)imidazo[1,5-a]pyridine-1-carboxylic Acids 5g–q,s;
General Procedure
13C NMR (DMSO-d6): δ = 12.2, 113.5, 118.6, 119.1, 123.5, 124.2, 133.9,
136.5, 164.0.
MS: m/z (%) = 178 (6) [M + 2]+, 177 (70) [M + 1]+, 160 (11) [M + 2 –
H2O]+, 159 (100) [M + 1 – H2O]+, 131 (7) [M + 1 – H2O – CO]+, 105 (5)
[M + 1 – H2O – CO – C2H2]+.
2,2,2-Trifluoro-1-imidazo[1,5-a]pyridin-1-ylethanone (6 mmol) was
dissolved in MeOH (20 mL) and a solution of NaOH (1.2 g, 30 mmol)
in water (20 mL) was added. The mixture was heated at reflux for 1 h,
then MeOH was evaporated, 10% aq citric acid was added dropwise to
the aqueous residue under cooling and stirring until precipitate was
obtained. The solid was filtered and washed with cold water three
times. The product was dried on air at 50–60 °C.
3-Ethylimidazo[1,5-a]pyridine-1-carboxylic Acid (5c)
Yield: 0.82 g (72%); light-brown solid; mp 167–169 °C.
3-(2-Methylpropyl)imidazo[1,5-a]pyridine-1-carboxylic Acid (5g)
1H NMR (DMSO-d6): δ = 1.33 (t, J = 7.4 Hz, 3 H), 2.99 (q, J = 7.4 Hz,
2 H), 6.9 (t, J = 6.6 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.98 (d, J = 8.8 Hz,
1 H), 8.32 (d, J = 6.6 Hz, 1 H), 12.06 (br s, 1 H).
13C NMR (DMSO-d6): δ = 10.9, 19.2, 113.44, 118.7, 119.4, 123.2, 124.1,
134.1, 140.9, 164.3.
MS: m/z (%) = 192 (11) [M + 2]+, 191 (100) [M + 1]+, 174 (12) [M + 2–
H2O]+, 173 (96) [M + 1 – H2O]+, 145 (5) [M + 1 – H2O – CO]+, 105 (6) [M
+ 1 – H2O – CO – C3H4]+.
The synthesis of this substance was reported by Bermudez,19 without
any characterization.
Yield: 1.11 g (85%); brown solid; mp 141–143 °C.
1H NMR (DMSO-d6): δ = 0.93 (d, J = 6.3 Hz, 6 H), 2.08–2.20 (m, 1 H),
2.89 (d, J = 7.0 Hz, 2 H), 6.87 (t, J = 6.6 Hz, 1 H), 7.15 (t, J = 7.6 Hz, 1 H),
7.99 (d, J = 8.8 Hz, 1 H), 8.39 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 22.27, 26.97, 27.34, 113.4, 118.8, 119.9,
123.4, 123.9, 133.9, 139.3, 164.4.
MS: m/z (%) = 220 (13) [M + 2]+, 219 (100) [M + 1]+, 202 (6) [M + 2 –
H2O]+, 201 (54) [M + 1 – H2O]+, 173 (2) [M + 1 – H2O – CO]+.
3-tert-Butylimidazo[1,5-a]pyridine-1-carboxylic Acid (5h)
Yield: 1.22 g (93%); beige solid; mp 298 °C (dec.).
1H NMR (CF3CO2D): δ = 1.52 (s, 1 H), 7.16 (t, J = 6.6 Hz, 1 H), 7.44 (t, J =
7.6 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 8.4 (d, J = 6.6 Hz, 1 H).
13C NMR (CF3CO2D): δ = 27.8, 36.4, 112.6, 121.5, 121.9, 126.3, 123.17,
132.5, 137.5, 149.6, 163.8.
3-Propylimidazo[1,5-a]pyridine-1-carboxylic Acid (5d)
Yield: 0.98 g (80%); light-brown solid; mp 145–146 °C.
1H NMR (DMSO-d6): δ = 0.94 (t, J = 6.8 Hz, 3 H), 1.71–1.83 (m, J =
7.2 Hz, 2 H), 2.96 (t, J = 7.1 Hz, 2 H), 6.87 (t, J = 6.6 Hz, 1 H), 7.15 (t, J =
7.6 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 8.35 (d, J = 6.6 Hz, 1 H), 12.18
(br s, 1 H).
MS: m/z (%) = 220 (12) [M + 2]+, 219 (100) [M + 1]+, 202 (5) [M + 2 –
H2O]+, 201 (36) [M + 1 – H2O]+, 105 (3).
13C NMR (DMSO-d6): δ = 13.7, 19.9, 27.5, 113.4, 118.7, 119.6, 123.3,
124.0, 134.8, 139.8, 164.3.
3-Cyclobutylimidazo[1,5-a]pyridine-1-carboxylic Acid (5i)
MS: m/z (%) = 206 (14) [M + 2]+, 205 (100) [M + 1]+, 188 (12) [M + 2 –
Yield: 1.08 g (83%); off-white solid; mp 177–179 °C.
H2O]+, 187 (96) [M + 1 – H2O]+, 159 (2) [M + 1 – H2O – CO]+.
1H NMR (DMSO-d6): δ = 1.87–1.98 (m, 1 H), 2.01–2.15 (m, 1 H), 2.37–
2.49 (m, 4 H), 3.90–4.02 (m, 1 H), 6.86 (t, J = 6.6 Hz, 1 H), 7.13 (t, J =
7.6 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 8.19 (d, J = 6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 18.3, 26.2, 30.5, 113.5, 118.9, 119.8, 123.2,
124.1, 134.1, 142.4, 164.4.
3-(1-Methylethyl)imidazo[1,5-a]pyridine-1-carboxylic Acid (5e)
Yield: 0.94 g (77%); beige solid; mp 182–183 °C.
1H NMR (DMSO-d6): δ = 1.32 (d, J = 6.2 Hz, 6 H), 3.45–3.56 (m, J =
6.2 Hz, 1 H), 6.89 (t, J = 6.6 Hz, 1 H), 7.16 (t, J = 8.8 Hz, 1 H), 7.99 (d, J =
8.8 Hz, 1 H), 8.39 (d, J = 6.6 Hz, 1 H), 12.08 (br s, 1 H).
MS: m/z (%) = 218 (12) [M + 2]+, 217 (100) [M + 1]+, 200 (12) [M + 2 –
H2O]+, 199 (48) [M + 1 – H2O]+, 171 (10) [M + 1 – H2O – CO]+.
13C NMR (DMSO-d6): δ = 20.4, 25.0, 113.4, 118.8, 119.4, 123.1, 123.9,
134.0, 144.3, 164.2.
3-Cyclopentylimidazo[1,5-a]pyridine-1-carboxylic Acid (5j)
MS: m/z (%) = 206 (12) [M + 2]+, 205 (100) [M + 1]+, 188 (8) [M + 2 –
Yield: 1.2 g (87%); white solid; mp 180–183 °C.
H2O]+, 187 (70) [M + 1 – H2O]+, 159 (2) [M + 1 – H2O – CO]+.
1H NMR (DMSO-d6): δ = 1.60–1.74 (m, 2 H), 1.74–1.85 (m, 2 H), 1.85–
1.99 (m, 2 H), 2.03–2.17 (m, 2 H), 3.48–3.60 (m, 1 H), 6.79 (t, J =
6.6 Hz, 1 H), 7.01 (t, J = 7.6 Hz, 1 H), 8.06 (d, J = 8.8 Hz, 1 H), 8.29 (d, J =
6.6 Hz, 1 H).
13C NMR (DMSO-d6): δ = 25.2, 30.4, 35.6, 113.1, 119.3, 122.9, 133.3,
142.5, 165.4.
3-Cyclopropylimidazo[1,5-a]pyridine-1-carboxylic Acid (5f)
Yield: 0.92 g (90%); brown solid; mp 175–176 °C.
1H NMR (DMSO-d6): δ = 0.88–0.99 (m, 2 H), 0.99–1.11 (m, 2 H), 2.29–
2.42 (m, 1 H), 6.91 (t, J = 6.6 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.97 (d,
J = 8.8 Hz, 1 H), 8.52 (d, J = 6.6 Hz, 1 H), 12.16 (br s, 1 H).
13C NMR (DMSO-d6): δ = 6.3, 6.7, 113.6, 118.8, 119.1, 123.0, 124.2,
134.2, 141.0, 164.1.
MS: m/z (%) = 232 (14) [M + 2]+, 231 (100) [M + 1]+, 214 (5) [M + 2 –
H2O]+, 213 (41) [M + 1 – H2O]+.
MS: m/z (%) = 204 (13) [M + 2]+, 203 (100) [M + 1]+, 186 (10) [M + 2 –
H2O]+, 185 (83) [M + 1 – H2O]+, 157 (6) [M + 1 – H2O – CO]+, 105 (3) [M
+ 1 – H2O – CO – C4H4]+.
The synthesis of this substance was reported by Trotter,4 without any
characterization.
3-Cyclohexylimidazo[1,5-a]pyridine-1-carboxylic Acid (5k)
Yield: 1.3 g (89%); beige solid; mp 189–190 °C.
1H NMR (DMSO-d6): δ = 1.16–1.32 (m, 1 H), 1.32–1.48 (m, 2 H), 1.48–
1.62 (m, 2 H), 1.62–1.71 (m, 1 H), 1.71–1.83 (m, 2 H), 1.83–2.00 (m,
2 H), 3.10–3.23 (m, 1 H), 6.79 (t, J = 6.6 Hz, 1 H), 7.01 (t, J = 7.6 Hz,
1 H), 8.06 (d, J = 8.8 Hz, 1 H), 8.29 (d, J = 6.6 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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D. O. Tverdiy et al.
Paper
Synthesis
13C NMR (DMSO-d6): δ = 25.6, 25.7, 30.5, 34.3, 113.4, 119.0, 120.0,
123.2, 123.9, 133.8, 143.7, 164.6.
MS: m/z (%) = 275 (17) [M + 2]+, 274 (100) [M + 1]+, 255 (6) [M + 2 –
H2O]+, 256 (32) [M + 1 – H2O]+, 230 (2) [M + 1 – H2O – CO]+.
MS: m/z (%) = 246 (17) [M + 2]+, 245 (100) [M + 1]+, 228 (6) [M + 2 –
H2O]+, 227 (34) [M + 1 – H2O]+.
3-(Trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylic Acid (5q)
Yield: 1.3 g (94%); white solid; mp 277 °C.
1H NMR (DMSO-d6): δ = 7.21 (t, J = 6.3 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H),
8.21 (d, J = 8.8 Hz, 1 H), 8.57 (d, J = 6.3 Hz, 1 H), 12.93 (br s, 1 H).
3-(2-Phenylethyl)imidazo[1,5-a]pyridine-1-carboxylic Acid (5l)
Yield: 1.47 g (92%); off-white powder; mp 175–177 °C.
1
1H NMR (DMSO-d6): δ = 3.11 (t, J = 7.2 Hz, 2 Н), 3.29 (t, J = 7.2 Hz, 2 Н),
6.85 (t, J = 6.6 Hz, 1 H), 7.11–7.21 (m, 2 H), 7.21–7.33 (m, 4 H), 7.99 (d,
J = 8.8 Hz, 1 H), 8.33 (d, J = 6.6 Hz, 1 H), 12.23 (br s, 1 H).
13C NMR (DMSO-d6): δ = 27.6, 32.4, 113.4, 118.7, 119.6, 123.3, 124.1,
126.1, 128.3, 128.5, 134.1, 139.3, 141.0, 164.2.
13C NMR (DMSO-d6): δ = 116.8, 119.2, 119.2 (q, JC–F = 266.0 Hz),
121.7, 123.6, 125.0 (q, 2JC–F = 41.0 Hz), 126.8, 135.7, 163.3.
19F NMR (DMSO-d6): δ = –62.46.
MS: m/z (%) = 178 (6) [M + 2]+, 177 (70) [M + 1]+, 160 (11) [M + 2 –
H2O]+, 159 (100) [M + 1 – H2O]+, 131 (7), 105 (5).
MS: m/z (%) = 268 (12) [M + 2]+, 267 (100) [M + 1]+, 250 (5) [M + 2 –
H2O]+, 249 (31) [M + 1 – H2O]+.
Imidazo[1,5-a]pyridine-1,3-dicarboxylic Acid (5s)
Yield: 1 g (81%); white solid; mp >300 °C.
1H NMR (CF3CO2D): δ = 7.67 (t, J = 4.9 Hz, 1 H), 7.92 (t, J = 7.4 Hz, 1 H),
8.57 (d, J = 8.4 Hz, 1 H), 9.52 (d, J = 4.9 Hz, 1 H).
13C NMR (CF3CO2D): δ = 117.0, 121.9, 124.4, 126.6, 128.5, 134.6, 137.6,
158.0, 163.1.
MS: m/z (%) = 208 (12) [M + 2]+, 207 (100) [M + 1]+, 189 (8) [M + 2 –
H2O]+, 190 (54) [M + 1 – H2O]+, 146 (3) [M + 1 – H2O – CO2]+, 145 (21)
[M + 1 – H2O – CO2]+, 117 (10) [M + 1 – H2O – CO2 – CO]+.
3-Phenylimidazo[1,5-a]pyridine-1-carboxylic Acid (5m)
Yield: 1.29 g (90%); off-white powder; mp 105–108 °C.
1H NMR (DMSO-d6): δ = 6.94 (t, J = 6.6 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H),
7.47–7.62 (m, 3 H), 7.76–7.83 (m, 2 H), 8.11 (d, J = 8.8 Hz, 1 H), 8.53
(d, J = 6.6 Hz, 1 H), 12.41 (br s, 1 H).
13C NMR (DMSO-d6): δ = 114.7, 119.1, 121.4, 123.5, 125.0, 128.4,
129.1, 129.1, 129.3, 134.9, 138.2, 164.2.
MS: m/z (%) = 240 (16) [M + 2]+, 239 (100) [M + 1]+, 222 (7) [M + 2 –
H2O]+, 221 (44) [M + 1 – H2O]+, 193 (5) [M + 1 – H2O – CO]+.
The synthesis of this substance was reported by Kamal7b without any
characterization.
Acknowledgment
We thank Azepine Ltd. for help with starting compounds and sol-
vents.
3-Pyridin-3-ylimidazo[1,5-a]pyridine-1-carboxylic Acid (5n)
Yield: 1.26 g (88%); pale yellow solid; mp 251–253 °C.
1H NMR (DMSO-d6): δ = 6.98 (t, J = 6.6 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H),
7.61 (t, J = 5.6 Hz, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 8.28 (d, J = 7.4 Hz, 1 H),
8.61 (d, J = 6.6 Hz, 1 H), 8.71 (d, J = 3.7 Hz, 1 H), 9.04 (s, 1 H), 12.51
(br s, 1 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561489.
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13C NMR (DMSO-d6): δ = 115.0, 119.0, 121.9, 123.7, 124.0, 125.3,
125.5, 135.2, 135.7, 135.8, 148.9, 149.9, 164.1.
Primary Data
MS: m/z (%) = 241 (15) [M + 2]+, 240 (100) [M + 1]+, 223 (4) [M + 2 –
H2O]+, 222 (32) [M + 1 – H2O]+, 194 (2) [M + 1 – H2O – CO]+.
Primary data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000084 and can
be cited using the following DOI: 10.4125/pd0080th.
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3-Pyridin-4-ylimidazo[1,5-a]pyridine-1-carboxylic Acid (5o)
Yield: 1.15 g (80%); yellow solid; mp 245–247 °C.
1H NMR (DMSO-d6): δ = 7.06 (t, J = 6.6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H),
7.92 (d, J = 2.8 Hz, 2 H), 8.2 (d, J = 8.8 Hz, 1 H), 8.67–8.81 (m, 3 H),
12.65 (br s, 1 H).
References
(1) Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei,
G.; Chavignon, O.; Teulade, J.-C.; Kerbal, A.; Essassi, E. M.;
Debouzy, J.-C.; Witvrouw, M.; Blache, Y.; Balzarini, J.; De Clercq,
E.; Chapet, J.-P. J. Med. Chem. 1996, 39, 2856.
(2) Kaminski, J. J.; Bristol, J. A.; Lovey, R. G.; Puchalsky, C.; Lovey, R.
G.; Elliot, A. J.; Guzik, H.; Solomon, D. M.; Conn, D. J.; Domalski,
M. S. J. Med. Chem. 1985, 28, 876.
13C NMR (DMSO-d6): δ = 115.4, 119.1, 122.0, 122.3, 124.0, 125.7,
135.3, 135.6, 136.4, 150.4, 164.0.
MS: m/z (%) = 241 (13) [M + 2]+, 240 (100) [M + 1]+, 222 (2) [M + 1 –
H2O]+, 197 (1) [M + 2 – H2O – C2H2]+, 196 (7) [M + 1 – H2O – C2H2]+.
3-(2-Chloropyridin-4-yl)imidazo[1,5-a]pyridine-1-carboxylic Acid
(5p)
(3) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999,
9, 97.
Yield: 1.48 g (90%); pale yellow solid; mp 255–257 °C.
(4) Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng,
J. Z.; Green, A. I.; Hartnett, J. C.; Kett, N. R.; Wu, Z.; Henze, D. A.;
Penna, K. D.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.;
Yeh, S.; Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T.
Bioorg. Med. Chem. Lett. 2011, 21, 2354.
1H NMR (DMSO-d6): δ = 7.08 (t, J = 6.6 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H),
7.93 (d, J = 2.8 Hz, 1 H), 7.97 (s, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 8.57 (d,
J = 2.8 Hz, 1 H), 8.80 (d, J = 6.6 Hz, 1 H), 12.67 (br s, 1 H).
13C NMR (DMSO-d6): δ = 114.7, 119.1, 121.4, 123.5, 125.0, 128.4,
129.1, 129.1, 129.3, 134.9, 138.2, 164.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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D. O. Tverdiy et al.
Paper
Synthesis
(5) Ford, N. F.; Browne, L. J.; Campell, T.; Gemenden, C.; Goldstein,
R.; Gude, C.; Waley, J. W. F. J. Med. Chem. 1985, 28, 164.
(6) (a) Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager,
A. J. Med. Chem. 1991, 2, 725. (b) Pettit, G. R.; Collins, J. C.;
Knight, J. C.; Herald, D. L.; Nieman, R. A.; Williams, M. D.; Pettit,
R. K. J. Nat. Prod. 2003, 66, 544. (c) Mohamed, M.; Goncalves, T.
P.; Whitby, R. J.; Sneddon, H. F.; Harrowven, D. C. Chem. Eur. J.
2011, 17, 13698. (d) Knueppel, D.; Martin, S. F. Angew. Chem. Int.
Ed. 2009, 48, 2569. (e) Markey, M. D.; Kelly, T. R. J. Org. Chem.
2008, 73, 7441.
(7) (a) Kamal, A.; Ramakrishna, G.; Raju, P.; Subba Rhao, A. V.;
Viswanath, A.; Lakshma Nayak, V.; Ramakrishna, S. Eur. J. Med.
Chem. 2011, 46, 2427. (b) Kamal, A.; Ramakrishna, G.; Ramaiah,
M. J.; Viswanath, A.; Rao, A. V. S.; Bagul, C.; Mukhopadyay, D.;
Pushpavalli, S. N. C. V. L.; Pal-Bhadra, M. Med. Chem. Commun.
2013, 4, 697. (c) Kamal, A.; Rao, A. V. S.; Nayak, V. L.; Reddy, N. V.
S.; Swapna, K.; Ramakrishna, G.; Alvala, M. Org. Biomol. Chem.
2014, 12, 9864. (d) Nirogi, R.; Mohammed, A. R.; Shinde, A. K.;
Bogaraju, N.; Gagginapalli, S. R.; Ravella, S. R.; Kota, L.;
Bhyrapuneni, G.; Muddana, N. R.; Benade, V.; Palacharla, R. C.;
Jayarajan, P.; Subramanian, R.; Goyal, V. K. Eur. J. Med. Chem.
2015, 103, 289.
(9) Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.; MacCoss,
M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.;
Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.;
Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2005, 15, 2129.
(10) Kovtun, Yu. P.; Prostova, Y. A. Chem. Heterocycl. Comp. 2000, 36,
557.
(11) Fos, E.; Bosca, F.; Mauleon, D.; Carganico, G. J. Heterocycl. Chem.
1993, 30, 473.
(12) Ashauer, U.; Wolff, C.; Haller, R. Arch. Pharm. 1986, 1, 43.
(13) Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009, 50, 4916.
(14) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 9, 2290.
(15) Schreber, S. L. Tetrahedron Lett. 1980, 1027.
(16) Meyers, A. I.; Marra, J. M. Tetrahedron Lett. 1985, 48, 5863.
(17) Khodakovskiy, P. V.; Volochnyuk, D. M.; Panov, D. M.; Pervak, I.
I.; Zarudnitskii, E. V.; Shishkin, O. V.; Yurchenko, A. A.;
Shivanyuk, A.; Tolmachev, A. A. Synthesis 2008, 948.
(18) (a) Arvapalli, V. S.; Chen, G.; Kosarev, S.; Tan, M. E.; Xie, D.; Yet,
L. Tetrahedron Lett. 2010, 51, 284. (b) Hickey, D. M. B.; Moody, C.
J.; Rees, C. W.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1982,
4.
(19) Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.; King, F. D.;
Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990, 33, 1924.
(8) (a) Markey, M. D.; Kelly, T. R. J. Org. Chem. 2008, 73, 7441.
(b) Wallach, O. Justus Liebigs Ann. Chem. 1877, 184, 1. (c) Bower,
J. D.; Ramage, C. R. J. Chem. Soc. 1955, 2834.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I