Aminocarbonylation of N -Containing Heterocycles with Aromatic Amines Using Mo(CO) 6

Article abstract of DOI:10.1055/s-0037-1609152

We describe herein the palladium-catalyzed aminocarbonylation of nitrogen-containing heterocycles with aniline derivatives using molybdenum hexacarbonyl as a CO solid source, expanding the scope of the limited examples. This method is compatible with a variety of substitutions on the aniline moiety. The simple reaction conditions include easily available Pd(dppf)Cl ₂ catalyst, DBU as base in DMF at 120 °C for 3 hours in sealed tube thereby leading to the isolation of 21 compounds with yields ranging from 18 to 82%. We also show that double aminocarbonylation reactions are possible in satisfactory yields regarding both coupling partners.

Full text of DOI:10.1055/s-0037-1609152

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
M. Mamone et al.
Paper
Synthesis
Aminocarbonylation of N-Containing Heterocycles with Aromatic
Amines Using Mo(CO)6
Marius Mamonea
Jessy Aziza
Julie Le Besconta,b
Sandrine Piguel*a,b
R
Pd(dppf)Cl2
Mo(CO)6
DBU
O
R
N
+
Br
N
N
H
DMF, 120 °C
sealed tube, 3 h
H2N
21 examples
18–82%
R = Me, Hal, CN, CO2Et, etc.
a Institut Curie, PSL Research University, CNRS, IN-
SERM, UMR9187-U1196, 91405 Orsay, France
b Université Paris Sud, Université Paris-Saclay, 91405
Orsay, France
sandrine.piguel@u-psud.fr
Received: 13.12.2017
Accepted after revision: 13.12.2017
Published online: 18.01.2018
ficient alternatives.7,8 In 2002, Larhed and co-workers pub-
lished the first palladium-catalyzed aminocarbonylation of
aryl halides with primary and secondary amines using
Mo(CO)6 as a solid CO source and a 2:1 mixture of
BINAP/Herrmann’s palladacycle precatalyst under micro-
wave irradiation.9 In 2003, an improved protocol using DBU
as base and THF as solvent was reported.10 This DBU-accel-
erated CO release allowed the use of poor nucleophilic
amines like aniline. Since then, Mo(CO)6 has gained increasing
attention as a CO precursor in palladium and non-palladium-
DOI: 10.1055/s-0037-1609152; Art ID: ss-2017-z0631-op
Abstract We describe herein the palladium-catalyzed aminocarbon-
ylation of nitrogen-containing heterocycles with aniline derivatives us-
ing molybdenum hexacarbonyl as a CO solid source, expanding the
scope of the limited examples. This method is compatible with a variety
of substitutions on the aniline moiety. The simple reaction conditions
include easily available Pd(dppf)Cl2 catalyst, DBU as base in DMF at 120
°C for 3 hours in sealed tube thereby leading to the isolation of 21 com-
pounds with yields ranging from 18 to 82%. We also show that double
aminocarbonylation reactions are possible in satisfactory yields regard-
ing both coupling partners.
CF3
S
O
OH
O
Key words heterocycles, nitrogen, aromatic amines, amide, carbon-
ylation, palladium, catalysis
N
N
N
H
N
H
N
S
O
O
O
The amide motif is an ubiquitous feature in both biolog-
ical systems and synthetic compounds such as pharmaceu-
ticals agents, agrochemicals, and polymers.1 Indeed, about
25% of commercially available drugs have an amide bond in
their backbone (Figure 1). The prevalence of the amide mo-
tif is mainly linked to its unique hydrogen bonding ability
as both acceptor and donor. Amide bond formation is a long
standing goal in organic synthesis. It generally relies on the
coupling of activated or non-activated carboxylic acids with
amines mediated by coupling agents (e.g., EDC, HOBt, CDI,
HATU, etc.) despite having poor atom economy and produc-
ing substantial waste.2 Therefore, alternative approaches for
amide bond formation with more respect to the green
chemistry concepts are still being pursued.3
Arava (Leflunonide)
Mobic (Meloxicam)
NO2
O
O
O
S
O
N
N
NH
H
Alinia/Kidonax (Nitazoxanide)
N
N
NH
N
N
Ph
HN
Ph
O
N
N
Gleevec (Imatinib)
F
Since the pioneering work of Schoenberg and Heck in
1974, Pd-catalyzed carbonylation has gained increasing at-
tention in the past decade and several procedures have
been reported using CO gas as carbonyl donor.4 However,
the requirement for specific equipment as well as the use of
odorless, toxic and flammable CO gas, are still major draw-
backs in this approach.5,6 Therefore, solid or liquid CO sur-
rogates such as chloroform, DMF, formic acid derivatives or
metal carbonyls have been explored and represent very ef-
HO
HO
CO2H
Lipitor (Atorvastatin)
Figure 1 Selection of FDA-approved drugs containing N-arylbenzamides
and N-arylheteroarenecarboxamides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
M. Mamone et al.
Paper
Synthesis
catalyzed aminocarbonylation processes.11 The utmost im-
portance of nitrogen-containing heterocycles in many fields
has inspired a wide array of synthetic work including
aminocarbonylation reactions, mainly with aliphatic amines.
Indeed, scarce examples of aminocarbonylation involving
both nitrogen-containing heterocycles and aromatic
amines have been reported and no systematic methods
have been developed.
In 2007, Letavic and Ly reported the aminocarbonylation
of various heteroaryl bromides with aliphatic amines using
Larhed’s procedure.12 In 2009, Queiroz and Begouin detailed
a single example of the aminocarbonylation of 2-bromo-
pyridine with p-anisidine according to Larhed’s procedure
using excess heterocycle, leading to a 60% yield of the aryl-
amide.13 A palladium-free method was also developed us-
ing a mixture of norbornadiene, DABCO, and TBAB in
diglyme at 140 °C and a single example of the aminocarbo-
nylation of 5-bromopyrimidine with benzylamine was de-
scribed.14 More recently, in 2014, Langer and co-workers
developed a convenient procedure using low nucleophilic
amines such as 2-aminobenzonitrile and the duet Pd(OAc)2/
cataCXium as catalyst in DMF. Interestingly, heteroaryl bro-
mides such as 5-bromoindole and 3-bromopyridine were
coupled albeit in moderate yield, 61% and 49% yield, respec-
tively, based on the deficit amine.15 In this context, we re-
port our efforts to expand the palladium-catalyzed amino-
carbonylation process to various nitrogen-containing het-
eroarenes and aniline derivatives using molybdenum
hexacarbonyl as a CO solid source.
As bromo derivatives are more easily available than
their iodo counterparts, they were initially used in these re-
actions. Initially, Lahred’s conditions10 for the aminocarbo-
nylation of 3-bromopyridine (1) with p-anisidine using
Mo(CO)6 as solid CO source and DBU as base in THF were
not suitable as no reaction was observed (Table 1, entry 1).
The system Herrmann’s palladacycle/t-Bu3PHBF4 used by
Letavic and Ly12 delivered the desired product 3 in a low
yield (Table 1, entry 2). The subsequent screening of palla-
dium/ligand sources under microwave irradiation in diox-
ane at 150 °C with a large excess of p-anisidine (5 equiv)
was investigated (Table 1). The use of electron-rich phos-
phine was really favorable for the reaction. Indeed, P(o-
tolyl)3 gave a moderate yield of 46% which was increased to
77% with XPhos [2-dicyclohexylphosphino-2′,4′,6′-triiso-
propylbiphenyl] and 80% with cataCXium A [di(1-adaman-
tyl)-n-butylphosphine] (entries 3–5). With bidentate dppb
[1,4-bis(diphenylphosphino)butane], a slightly lower yield
of compound 3 was obtained (entry 6). Decreasing both the
Table 1 Aminocarbonylation of 3-Bromopyridine
[Pd]
Mo(CO)6
DBU
O
O
O
Br
+
N
H
Solvent
H2N
N
N
1
2
3
Entry
Pd source
Ligand
Solvent, temp
Yield (%)c
1a
2a
Pd(OAc)2 (10 mol%)
–
THF, 100 °C
0
30
46
80
77
64
47d
81
67
43
46
39
<10
39
21
Herrmann’s palladacycle
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (5 mol%)
t-Bu3PHBF4
THF, 125 °C
3a
P(o-tolyl)3 (20 mol%)
dioxane, 150 °C
dioxane, 150 °C
dioxane, 150 °C
dioxane, 150 °C
dioxane, 150 °C
DMF, 120 °C
DMF, 120 °C
DMF, 120 °C
dioxane, 120 °C
DMF, 120 °C
DMF, 120 °C
DMF, 100 °C
DMF, 80 °C
4a
cataCXium A (20 mol%)
5a
XPhos (20 mol%)
6a
dppb (20 mol%)
7a
XPhos (10 mol%)
8b
Pd(dppf)Cl2 (5 mol%)
–
–
–
–
–
–
–
–
9b
Herrmann’s palladacycle (5 mol%)
dppf Pd G3
10b
11b
12b
13b
14b
15b
Pd(dppf)Cl2 (5 mol%)
Pd(dppf)Cl2 (2.5 mol%)
Pd(dppf)Cl2 (1 mol%)
Pd(dppf)Cl2 (5 mol%)
Pd(dppf)Cl2 (5 mol%)
a Reaction conditions: 3-bromopyridine (0.5 mmol), p-anisidine (5 equiv), Mo(CO)6 (0.37 equiv), Pd/ligand, solvent, 150 °C, microwaves, 1 h.
b Reaction conditions: 3-bromopyridine (0.63 mmol), p-anisidine (2 equiv), Mo(CO)6 (0.37 equiv), [Pd], DBU (2.2 equiv), DMF, 120 °C, 3 h, sealed tube.
c Isolated yield.
d 2 equiv of amine were used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
M. Mamone et al.
Paper
Synthesis
catalyst loading to 5 mol% and the amount of amine to 2
equiv were deleterious for the reaction, giving amide 3 in
only 47% yield (entry 7). Although good yields were ob-
tained, all the above conditions required both excess amine
(5 equiv) and high catalyst loading. Concurrently, we inves-
tigated conventional heating conditions along with a re-
duced quantity of amine. We performed aminocarbonyla-
tion using ‘precatalyst’ Pd–ligand complex Pd(dppf)Cl2
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium)
with DBU as base and only 2 equiv of amine in DMF at
120 °C. The desired product 3 was isolated in 81% yield after
3 hours only (entry 8). Replacing Pd(dppf)Cl2 by Herr-
mann’s palladacycle or Buchwald’s palladium precatalyst5a
resulted in a lower yield of aminocarbonylation (respective-
ly 67% and 43%, entries 9 and 10). DMF proved to be the
best solvent as reaction in dioxane afforded compound 3 in
only 46% yield (entry 10). Decreasing the catalytic loading
to 1 mol% and the temperature dramatically affected the
outcome of the reaction (entries 12–13 and 14–15). Finally,
we identified Pd(dppf)Cl2 (5 mol%), Mo(CO6) and DBU in
DMF at 120 °C as the optimum conditions for the aminocar-
bonylation of 3-bromopyridine (1) with 2 equiv of p-anisi-
dine (2) since they do not require any additional phosphine
ligand and large excess of amine.
Having determined the optimal conditions for the ami-
nocarbonylation, we first set out to probe the scope of this
protocol regarding the nitrogen-containing heteroarene
partner. The results are shown in Scheme 1. The reactivity
of 3-iodopyridine and 3-chloropyridine was also studied.
The aminocarbonylation reaction of 3-iodopyridine gave
the amide derivative 3 in a slightly lower yield (79%),
whereas no product was formed when using the corre-
sponding chloride. In addition, all positions of the pyridine
ring can efficiently be functionalized, 2-bromopyridine be-
ing the least reactive furnishing product 4 in 55% yield; 3- and
6-bromoquinoline were also reactive giving compounds 6
and 7 in 81% and 73% yields, respectively. Interestingly, 6-
bromo-3-MEM-3H-imidazo[4,5-b]pyridine was also com-
patible with the reaction conditions afforded the expected
compound 8 in 61% yield. Noteworthy was the more com-
plex dihalogenated heteroaryl, 6-bromo-2-(5-bromopyri-
din-3-yl)-3-MEM-3H-imidazo[4,5-b]pyridine, which un-
derwent a double aminocarbonylation to afford the di-ami-
dated compound 9 in a satisfactory 47% yield, highlighting
the efficacy of the amidation process on two different
heterocycles. Unfortunately, with other nitrogen-contain-
ing heterocycles such as 6-chloro-9-methyl-9H-purine or
2-bromobenzimidazole, either the aminated product was
isolated or no reaction occurred even after prolonged reac-
tion time (not shown).
PdCl2dppf (5 mol%)
Mo(CO)6 (0.37 equiv)
DBU (2.2 equiv)
OMe
OMe
O
O
Het Br
+
DMF, 120 °C
sealed tube, 3 h
H2N
Het
N
H
2
OMe
OMe
OMe
O
O
N
H
N
H
N
H
N
N
N
5, 71%
3
4, 55%
Het-Br 81%
Het-I 79%
Het-Cl 0%
OMe
OMe
O
O
N
H
N
H
N
N
6, 81%
7, 73%
OMe
O
N
N
N
H
N
8, 61%
MEM
O
OMe
O
HN
N
N
N
H
N
N
MeO
MEM
9, 47%
Scheme 1 Aminocarbonylation of heteroaryl bromides with p-anisi-
dine; yields are calculated on isolated products (average of two runs)
rich and electron-deficient anilines reacted with 3-bro-
mopyridine in good yields, with substitution being tolerat-
ed at each of the ortho, meta and para positions. These con-
ditions proved to be compatible with the presence of im-
portant functional groups such as ester (78%), a cyano
group (64%) and halides (36–80%) on the aniline moiety,
which may be subject to further transformations.
Nitrogen-containing heteroaryl like indole seems to be
less reactive and only 18% of the coupling product 19 was
isolated with incomplete conversion even after a prolonged
reaction time. Interestingly, starting from the 4-aminophe-
nol, the aminocarbonylation product 20 was obtained ex-
clusively and no traces of alkoxycarbonylation were detect-
ed. This result is in sharp contrast to the work of Alper and
co-workers who carried out the selective alkoxycarbonyla-
tion of aryl iodines using Pd(OAc)2 and 1,3-bis(diphenyl-
phosphino)propane (dppp), an electron-poor phosphine li-
gand. Conversely, the use of electron-rich ligands, in addi-
tion of DBU, was in favor of aminocarbonylation.16 An
aliphatic amine was also reactive in these conditions lead-
ing to amide 21 in 68% yield. Finally, 2-aminopyridine and
2,6-diaminopyridine proved to be really good substrates for
this reaction. In particular, the double aminocarbonylation
Then, we investigated the scope of aminocarbonylation
with various substituted anilines. The results are reported
in Scheme 2. The reaction with aniline gave the N-phenyl-
nicotinamide (10) with a good yield of 75%. Both electron-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
M. Mamone et al.
Paper
Synthesis
R
PdCl2dppf (5mol%)
Mo(CO)6 (0.37equiv)
DBU (2.2equiv)
R
O
Br
+
N
H
N
DMF, 120 °C
sealed tube, 3 h
H2N
N
1
Cl
Br
F
O
O
O
O
N
H
N
H
N
N
H
H
N
N
N
N
12, 53%
13, 36%
10, 75%
11, 80%
F
CO2Et
O
O
O
O
N
H
N
H
N
H
CF3
N
H
F
N
N
N
N
15, 81%
16, 74%
17, 78%
14, 82%
CN
O
OH
O
O
N
N
H
N
H
N
N
N
18, 64%
19, 18%
20, 63%
O
O
O
O
N
N
N
H
N
N
N
H
H
H
N
N
N
N
22, 82%
23, 62%
21, 68%
Scheme 2 Aminocarbonylation of 3-bromopyridine with various (hetero)arylamines
took place in a very good 62% yield with 2,6-diamino-
pyridine giving a new and easy access to polypyridine-type
ligands 23.
Compounds 3,17 4,13 5,18 10,19 11,20 12,21 14,22 18,23 19,19 21,24 and 2225
showed satisfactory spectroscopic data in agreement with those re-
ported in the literature.
In conclusion, optimized palladium-catalyzed amino-
carbonylation conditions were applied to various nitrogen-
containing heterocycles with aniline derivatives expanding
the scope of the limited examples. This methodology relies
on the use of Mo(CO)6 as solid CO source and DBU as base
and does not require additional ligand or sophisticated
palladium complexes. The reaction tolerates a wide range of
functional groups on the aniline moieties thereby leading
to 21 N-arylamides with 18–82% yields. We also showed
that double aminocarbonylation reactions can be accom-
plished in satisfactory yields regarding both coupling part-
ners thereby giving a new access to more complexes mole-
cules.
Aminocarbonylation; General Procedure
In a sealed tube and under argon inlet, aryl halide (1 equiv), PdCl2dppf
(5 mol%), Mo(CO)6 (0.37 equiv), and the amine (2.0 equiv) were
mixed. The tube was evacuated and backfilled with argon (3 ×).
Anhyd DMF (2 mL) was added and the mixture was stirred at r.t. for 1
min. DBU (2.2 equiv) was added and the reaction vessel was then
capped. The mixture was stirred at 120 °C for 3 h in a preheated oil
bath. After cooling to r.t., CH2Cl2 was added to the mixture, which was
filtered through Celite. The solvent was evaporated under reduced
pressure and the mixture was extracted (EtOAc) and the organic lay-
ers dried (MgSO4). The solvent was evaporated under reduced pres-
sure and the crude residue was purified by flash chromatography
(silica gel, CH2Cl2/MeOH).
N-(4-Methoxyphenyl)quinoline-3-carboxamide (6)
Starting from 3-bromoquinoline (132 mg, 0.63 mmol), flash chroma-
tography afforded 6 (143 mg, 81%) as a white solid; mp 175 °C.
1H NMR (300 MHz, DMSO-d6): δ = 10.39 (s, 1 H), 9.36 (d, J = 2.2 Hz, 1
H), 8.93 (d, J = 1.8 Hz, 1 H), 8.12 (dd, J = 7.5, 5.7 Hz, 2 H), 7.93–7.85 (m,
1 H), 7.76–7.67 (m, 3 H), 7.01–6.92 (m, 2 H), 3.77 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 163.6, 155.8, 149.1, 148.5, 135.9,
132.0, 131.3, 129.2, 128.8, 127.8, 127.5, 126.5, 122.0, 113.9, 55.2.
MS (ES+): m/z (%) = 279.1 (100) [M + H]+.
Commercially available reagents and solvents were used without fur-
ther purification. Yields refer to isolated and purified products. Reac-
tions were monitored by TLC carried out on 60F-254 silica gel plates
and visualized under UV light at 254 and 365 nm. Column chromatog-
raphy was performed using silica gel 60 (40–63 mm, 230–400 mesh
ASTM) at medium pressure. 1H and 13C NMR use residual non-deuter-
ated solvents as references. Melting points were measured with a Stu-
art SMP30. HRMS were measured by a TOF spectrometer using elec-
trospray ionization (ESI).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
M. Mamone et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H+] calcd for C17H15N2O2: 279.1134; found:
279.1125.
1H NMR (300 MHz, MeOH-d4): δ = 9.08 (d, J = 1.6 Hz, 1 H), 8.73 (dd,
J = 4.9, 1.4 Hz, 1 H), 8.38–8.32 (m, 1 H), 7.71–7.64 (m, 2 H), 7.59 (dd,
J = 7.5, 5.0 Hz, 1 H), 7.56–7.48 (m, 2 H).
13C NMR (75 MHz, MeOH-d4): δ = 166.3, 152.9, 149.4, 138.9, 137.2,
N-(4-Methoxyphenyl)quinoline-6-carboxamide (7)
132.8, 132.5, 125.1, 123.8, 118.3.
Starting from 6-bromoquinoline (132 mg, 0.63 mmol), flash chroma-
MS (ES+): m/z (%) = 279 (100) [M + 2 H]+.
tography afforded 7 (128 mg, 73%) as a white solid; mp 194 °C.
1H NMR (300 MHz, DMSO-d6): δ = 10.41 (s, 1 H), 9.01 (dd, J = 4.0, 1.3
Hz, 1 H), 8.62 (d, J = 1.1 Hz, 1 H), 8.53 (d, J = 8.1 Hz, 1 H), 8.27 (dd,
J = 8.8, 1.6 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.79–7.70 (m, 2 H), 7.63
(dd, J = 8.3, 4.2 Hz, 1 H), 7.01–6.90 (m, 2 H), 3.76 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 164.7 and 164.6, 155.7, 152.2,
148.8, 137.2, 132.9 and 132.9, 132.2 and 132.1, 129.1, 128.3, 128.1,
127.1, 122.3, 122.0 and 121.9, 113.8, 55.2.
HRMS (ESI): m/z [M + H+] calcd for C12H10N2OBr: 276.9976; found:
276.9983.
N-(2,5-Difluorophenyl)nicotinamide (15)
Starting from 3-bromopyridine (100 mg, 0.63 mmol), flash chroma-
tography afforded 13 (121 mg, 81%) as a white solid; mp 146 °C.
1H NMR (300 MHz, MeOH-d4): δ = 9.09 (d, J = 1.7 Hz, 1 H), 8.74 (dd,
J = 4.9, 1.5 Hz, 1 H), 8.37–8.32 (m, 1 H), 7.76 (ddd, J = 9.5, 6.0, 3.2 Hz, 1
H), 7.59 (dd, J = 7.9, 5.0 Hz, 1 H), 7.11 (dt, J = 9.6, 4.9 Hz, 1 H), 7.04–
6.92 (m, 1 H).
MS (ES+): m/z (%) = 279.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C17H15N2O2: 279.1134; found:
279.1134.
13C NMR (75 MHz, MeOH-d4): δ = 166.6, 159.7 (dd, J = 240.3, 2.4 Hz),
153.1, 152.6 (dd, J = 242.5, 2.9 Hz), 149.6, 137.5, 131.85, 127.9 (dd,
J = 14.1, 11.4 Hz), 125.2, 117.4 (dd, J = 22.8, 9.7 Hz), 113.6 (dd, J = 24.5,
7.9 Hz), 113.1 (dd, J = 28.3, 1.6 Hz).
MS (ES+): m/z (%) = 235.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C12H9N2OF2: 235.0683; found:
3-[(2-Methoxyethoxy)methyl]-N-(4-methoxyphenyl)-3H-imid-
azo[4,5-b]pyridine-6-carboxamide (8)
Starting from 6-bromo-3-[(2-methoxyethoxy)methyl]-3H-imid-
azo[4,5-b]pyridine (184 mg, 0.64 mmol), flash chromatography af-
forded 8 (140 mg, 61%) as a white solid; mp 122 °C.
1H NMR (300 MHz, CDCl3): δ = 8.99 (d, J = 1.4 Hz, 1 H), 8.58 (d, J = 1.2
Hz, 1 H), 8.28 (s, 1 H), 8.24 (s, 1 H), 7.63–7.55 (m, 2 H), 6.96–6.88 (m, 2
H), 5.78 (s, 2 H), 3.83 (s, 3 H), 3.75–3.70 (m, 2 H), 3.53–3.49 (m, 2 H),
3.33 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.7, 156.3, 148.4, 145.8, 145.2, 133.7,
131.2, 126.6, 126.4, 122.5, 113.8, 72.9, 71.3, 68.9, 58.8, 55.2.
MS (ES+): m/z (%) = 357.2 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C18H21N4O4: 357.1563; found:
235.0685.
N-[3-(Trifluoromethyl)phenyl]nicotinamide (16)
Starting from 3-bromopyridine (100 mg, 0.63 mmol), flash chroma-
tography afforded 16 (126 mg, 74%) as a white solid; mp 149 °C.
1H NMR (300 MHz, MeOH-d4): δ = 9.10 (d, J = 1.6 Hz, 1 H), 8.73 (dd,
J = 4.9, 1.4 Hz, 1 H), 8.41–8.31 (m, 1 H), 8.15 (br s, 1 H), 7.95 (d, J = 8.2
Hz, 1 H), 7.63–7.52 (m, 2 H), 7.45 (d, J = 7.8 Hz, 1 H).
357.1555.
13C NMR (75 MHz, MeOH-d4): δ = 166.5, 153.0, 149.5, 140.6, 137.4,
132.4, 132.2 (q, J = 32.2 Hz), 130.8, 125.5 (q, J = 271.5 Hz), 125.2,
125.1, 122.0 (q, J = 3.9 Hz), 118.4 (q, J = 4.1 Hz).
MS (ES+): m/z (%) = 267.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C13H10N2OF3: 267.0745; found:
3-[(2-Methoxyethoxy)methyl]-N-(4-methoxyphenyl)-2-{5-[(4-
methoxyphenyl)carbamoyl]pyridin-3-yl}-3H-imidazo[4,5-b]-
pyridine-6-carboxamide (9)
Starting
from
6-bromo-2-(3-bromophenyl)-3-[(2-methoxye-
267.0750.
thoxy)methyl]-3H-imidazo[4,5-b]pyridine (114 mg, 0.26 mmol),
flash chromatography afforded 9 (71 mg, 47%) as a white solid; mp
209 °C.
Ethyl 4-(Nicotinamido)benzoate (17)
Starting from 3-bromopyridine (100 mg, 0.63 mmol), flash chroma-
tography afforded 17 (133 mg, 78%) as a grey solid; mp 125 °C.
1H NMR (300 MHz, DMSO-d6): δ = 10.89 (br s, 1 H), 9.20 (s, 1 H), 8.83
(d, J = 4.2 Hz, 1 H), 8.45 (d, J = 7.9 Hz, 1 H), 7.97 (s, 4 H), 7.69 (dd,
J = 7.8, 5.0 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
1H NMR (300 MHz, DMSO-d6): δ = 10.55 (s, 1 H), 10.37 (s, 1 H), 9.38
(d, J = 1.8 Hz, 1 H), 9.31 (d, J = 1.7 Hz, 1 H), 9.05 (d, J = 1.7 Hz, 1 H),
8.95–9.91 (m, 1 H), 8.77 (d, J = 1.7 Hz, 1 H), 7.72 and 7.71 (2d, J = 9.0
Hz, 4 H), 6.97 and 9.96 (2d, J = 9.0 Hz, 4 H), 5.84 (s, 2 H), 3.83–3.78 (m,
2 H), 3.76 (s, 6 H), 3.50–3.45 (m, 2 H), 3.17 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 165.3, 164.0, 151.0, 147.7, 143.2,
137.2, 130.8, 130.1, 125.0, 124.1, 119.7, 60.5, 14.2.
MS (ES+): m/z (%) = 271.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C15H15N2O3: 271.1083; found:
13C NMR (75 MHz, MeOH-d4): δ = 163.8, 163.7, 162.9, 162.8, 155.9,
155.7, 153.2, 151.6, 150.2, 150.2, 145.0, 136.0, 133.5, 132.1, 131.8,
130.8, 126.9, 126.7, 125.3, 122.0, 121.9, 113.9, 113.8, 72.0, 70.9, 68.3,
66.7, 66.7, 58.1, 55.2.
MS (ES+): m/z (%) = 583.2 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C31H31N6O6: 583.2305; found:
271.1075.
583.2309.
N-(4-Hydroxyphenyl)nicotinamide (20)
Starting from 3-bromopyridine (100 mg, 0.63 mmol), flash chroma-
tography afforded 20 (133 mg, 63%) as a grey solid; mp >250 °C.
N-(4-Bromophenyl)nicotinamide (13)
1H NMR (300 MHz, DMSO-d6): δ = 10.22 (s, 1 H), 9.31 (s, 1 H), 9.08 (d,
J = 1.4 Hz, 1 H), 8.74 (dd, J = 4.7, 1.2 Hz, 1 H), 8.29–8.23 (m, 1 H), 7.59–
7.49 (m, 3 H), 6.79–6.71 (m, 2 H).
Starting from 3-bromopyridine (100 mg, 0.63 mmol), flash chroma-
tography afforded 13 (63 mg, 36%) as a beige solid; mp 174 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
M. Mamone et al.
Paper
Synthesis
13C NMR (75 MHz, DMSO-d6): δ = 163.5, 154.0, 151.9, 148.6, 135.3,
130.8, 130.4, 123.5, 122.3 (2 C), 115.1 (2 C).
MS (ES+): m/z (%) = 215.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C12H11N2O2: 215.0821; found:
(3) For selected reviews: (a) Roy, S.; Roy, S.; Gribble, G. W. Tetrahe-
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Campagne, J. M. Chem. Rev. 2016, 116, 12029.
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215.0816.
N,N′-(Pyridine-2,6-diyl)dinicotinamide (23)
Starting from 3-bromopyridine (200 mg, 1.27 mmol), flash chroma-
tography afforded 23 (126 mg, 62%) as a white solid; mp 254 °C.
(6) Takacs, A.; Jakab, B.; Petz, A.; Kollar, L. Tetrahedron 2007, 63,
10372.
(7) (a) Morimoto, T.; Kakiuchi, K. Angew. Chem. Int. Ed. 2004, 43,
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1H NMR (300 MHz, DMSO-d6): δ = 10.85 (s, 1 H), 9.12 (d, J = 1.8 Hz, 1
H), 8.77 (dd, J = 4.8, 1.6 Hz, 1 H), 8.35–8.30 (m, 1 H), 7.98–7.87 (m, 1
H), 7.56 (dd, J = 7.9, 4.8 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 164.7, 152.4, 150.3, 149.0, 140.2,
135.7, 129.9, 123.5, 111.7.
MS (ES+): m/z (%) = 320.2 (100) [M + H]+.
HRMS (ESI): m/z [M + H+] calcd for C17H14N5O2: 320.1147; found:
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320.1151.
Funding Information
French program ‘Investissement d’Avenir – Institut Carnot’ managed
by the National Research Agency (ANR-11-CARN-008-01).
N
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l
Research
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e
n
c
y
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N
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A
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0
8-01)
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(13) Begouin, A.; Queiroz, M.-J. R. P. Eur. J. Org. Chem. 2009, 2820.
(14) Iranpoor, N.; Firouzabadi, H.; Motevalli, S.; Talebi, M. Tetrahe-
dron 2013, 69, 418.
Acknowledgment
M. M. and J. A. thank the funding source for post-doctoral fellowships.
(15) Wu, X.-F.; Oschatz, S.; Sharif, M.; Beller, M.; Langer, P. Tetrahe-
dron 2014, 70, 23.
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2010139966, 2010.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609152.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F