One-pot access to a library of structurally diverse nicotinamide derivatives via a three-component formal Aza [3 + 3] cycloaddition

Article abstract of DOI:10.1021/co300081k

The three-component formal [3 + 3] aza-annulation between chalcones, β-ketoamides, and ammonium acetate in the presence of CAN as a Lewis acid affords good to excellent yields of highly substituted nicotinamides or their fused derivatives. This transformation leads to the formation of one C-C and two C-N bonds in a single synthetic operation and involves up to five individual steps.

Full text of DOI:10.1021/co300081k

Research Article
pubs.acs.org/acscombsci
One-Pot Access to a Library of Structurally Diverse Nicotinamide
Derivatives via a Three-Component Formal Aza [3 + 3] Cycloaddition
Giammarco Tenti, Ma Teresa Ramos, and J. Carlos Menendez*
́
́ ́
Departamento de Química Organica y Farmaceutica, Universidad Complutense, 28040 Madrid, Spain
S
* Supporting Information
ABSTRACT: The three-component formal [3 + 3] aza-
annulation between chalcones, β-ketoamides, and ammonium
acetate in the presence of CAN as a Lewis acid affords good to
excellent yields of highly substituted nicotinamides or their
fused derivatives. This transformation leads to the formation of
one C−C and two C−N bonds in a single synthetic operation
and involves up to five individual steps.
KEYWORDS: multicomponent reactions, pyridine synthesis, [3 + 3]aza-annulations
minimizing intermediate purification operations and waste
INTRODUCTION
■
generation from organic solvents and chromatographic sta-
tionary phases. Multicomponent reactions (MCRs) are
particularly important in this field and can be defined as
convergent processes that combine three or more reagents in a
single synthetic operation leading to a product that contains
significant fragments of all components.13,14 The development
and application in synthesis of new multicomponent reactions
is an important part of the research carried out in
pharmaceutical companies for library preparation in the context
of drug discovery15−17 and, since heterocycles are key structural
fragments of at least 60% of all known drugs and agrochemicals,
the application of the MCR methodology in heterocycle
synthesis can be considered crucial. While MCRs have been
often applied to pyridine synthesis (for leading references, see
refs 18 and 19) there is very little precedent for their use in the
preparation of nicotinamides.20 In this context, we report here a
new multicomponent reaction that allows a very efficient
preparation of highly substituted nicotinamides and their fused
derivatives from simple, acyclic starting materials.
Pyridine is one of the most important nitrogen heterocycles
both in academic and industrial environments, and this has led
to the development of a huge number of methods for its
synthesis, which have been reviewed recently.1−3 Besides their
use as catalysts, as part of supramolecular scaffolds and in the
preparation of new materials, pyridine derivatives are of interest
mainly because of their plethora of biological activities. In fact,
pyridine satisfies the definition “a single molecular framework
able to provide ligands for diverse receptors”, and therefore, it
can be considered as a privileged structure in drug discovery.4
Nicotinic acid derivatives and, especially, nicotinamides
constitute one of the most important families of biologically
relevant compounds containing a pyridine ring. They are
members of the B-vitamin group and play a key role in many
essential metabolic processes. The NAD/NADP coenzymes are
nicotinamide derivatives, leading to many potential targets for
interference with drugs.5 Besides, a number of derivatives of
nicotinamide have demonstrated pharmacological activity at
other types of targets. Thus, nicorandil is an established drug
acting as a selective activator of ATP-dependent potassium
channel that is employed in the treatment of cardiac ischemia.6
Many other pharmacologically relevant nicotinamides have
been described, including antiarrythmic compounds acting by
inhibition of the sodium−calcium exchanger (NCX),7 anti-
cancer compounds acting by inducing apoptosis8 or by
inhibiting vascular endothelial growth factor (VEGF)-induced
angiogenesis,9 anxiolytic, and antidepressant activity associated
to the inhibition of Type 5 metabotropic glutamate receptors
(mGluR5)10 and inhibitors of the gastric H+/K+ ATPase acting
as antiulcer agents.11
RESULTS AND DISCUSSION
■
Our method is based on the reaction between chalcones, β-
ketoamides and ammonium acetate, as an ammonia source.
The required chalcones (compounds 1) were of commercial
origin or were obtained by aldol condensation between
phenones and benzaldehydes under standard conditions.21−24
On the other hand, β-ketoamides were either obtained
commercially or prepared by treatment of primary or secondary
amines with 2,2,6-trimethyl-1,3-dioxin-4-one in conditions
recently developed by our group that involve the presence of
sodium acetate, which leads to the formation of an intermediate
mixed anhydride and allows the use of milder temperature
Contemporary organic synthesis is driven by traditional
concepts such as reactivity and selectivity, and also by economic
and environmental concerns. In this connection, the need to
optimize synthetic efficiency has led to the development of the
concept of multibond forming reactions,12 which achieve the
generation of several bonds in a single operation, thereby
Received: August 1, 2012
Revised: September 3, 2012
Published: September 6, 2012
© 2012 American Chemical Society
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conditions than alternative protocols.25 β-Oxoanilides were also
prepared by a literature method.26
synthesis from chalcone and acetoacetamide in the presence of
piperidine.30 While subsequent experiments showed that the
use of a higher catalyst load (entry 2, Table 1) or a more
concentrated solution (entry 3, Table 1) did not greatly
improve the results, a longer reaction time (15 h) was found to
be highly beneficial, leading almost exclusively to the target
compound 3a (entry 4, Table 1). A control experiment carried
out under the same conditions but in the absence of catalyst
also led to consumption of the starting materials and to the
formation of 3a, but in this case a higher amount of the side
product 5 was observed (entry 5, Table 1). Therefore,
subsequent experiments were performed in the presence of
10% CAN.
Having established the optimal conditions for nicotinamide
synthesis, we undertook an exploration of the scope of the
method. As shown in Scheme 2 and Table 2, the reaction
Scheme 2. Three-Component Synthesis of Nicotinamide
Derivatives
Figure 1. Building blocks employed in this work for the synthesis of
nicotinamides.
With suitable starting materials in hand, we investigated the
three-component reaction that constituted our goal. For the
initial optimization study, we examined the reaction between
chalcone, acetoacetamide and ammonium acetate. The first
experiment (entry 1, Table 1) was performed in refluxing
normally proceeded in good to excellent yields, and tolerated
well the presence of either electron-withdrawing or electron-
releasing groups at the chalcone aromatic rings. Ortho-
substitution at the R1 substituent (compound 3h) led to a
decrease in yield due to steric hindrance, but it had little effect
on the other aromatic ring (substituent R3), as shown by the
85% yield obtained for compound 3g. The main limitation of
the method came from the presence of substituents different
from hydrogen at R2, which was clearly detrimental for yield
and which could not be overcome in spite of having attempted
many different conditions (compound 3i). On the other hand,
while R4 was methyl in most cases due to a better accessibility
of the starting materials, we verified that the presence of other
substituents was also possible (compounds 3l−3n). Finally, the
amide nitrogen could be unsubstituted (compounds 3a−i),
monosubstituted with alkyl (3j) or aryl (3k−n) groups or
disubstituted (3o−q). Compound 3a had been prepared by a
related two-component reaction starting from chalcone and 2-
methylcrotonamide, albeit in a modest 36% yield.31
To prove the ability of the method to introduce further
structural diversity in the nicotinamide derivatives, we
examined the preparation of compounds bearing substituents
other than phenyl at the pyridine C-4 position by use of
suitably modified chalcones. This way, we prepared compounds
3r and 3s, with a heterocyclic moiety at C-4, and 3t and 3u,
with a styryl chain. In all these cases, the reaction time was 24 h
and yields were around 70% (Figure 2).
Table 1. Results Obtained under the Optimal Conditions in
the Presence or Absence of CAN
entry
conditions
4/3a/5
1
2
3
4
5
CAN (10%), EtOH, reflux, 4 h
CAN (20%), EtOH, reflux, 4 h
CAN (10%), EtOH, reflux, 4 h
41:45:14
30:55:15
40:48:12
0:95:5
a
CAN (10%), EtOH, reflux, 15 h
EtOH, reflux, 15 h
0:76:24
a
2 M solution of the reagents (in all the other experiments, reagent
concentration was 1 M).
ethanol and in the presence of ceric ammonium nitrate because
of our experience in the use of this reagent as a catalyst in a
somewhat related tetrahydropyridine synthesis from β-
dicarbonyl compounds, acrolein, and primary amines in the
presence of ethanol27−29 and provided a rather complex
mixture of the desired compound 3a, the corresponding
dihydropyridine 4 and a small amount of compound 5. The
latter compound arises from the Robinson annelation between
the chalcone and acetoacetamide without incorporation of
ammonia, and was unambiguously identified by its independent
Scheme 1. Products Observed during the Optimization Studies
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Finally, we also examined briefly the preparation of fused
pyridines by employing a β-ketolactam as the starting material.
To this end, we prepared compounds 6 following a literature
procedure32 and studied their reaction with chalcone 1a and
ammonium acetate in refluxing ethanol. As shown in Scheme 3,
Table 2. Scope and Yields Obtained in the Synthesis of
Substituted Nicotinamides
Scheme 3. Synthesis of Fused Dihydronicotinamide-Type
Compounds from a β-Ketolactam
in this case the main products were the 1,6-naphthyridine
derivatives 7, containing a fused dihydropyridine substructure,
together with a small amount of the corresponding pyridine 8b
for R = H.
It is interesting to note that a similar reaction involving the
use of primary amines instead of ammonia has been found to
give cyclohexene derivatives rather than the pyridines obtained
in the present work.33 Thus, the exquisite balance between the
two chemodivergent pathways involving [3 + 3] and aza-[3 +
3] formal cycloadditions, respectively, seems to depend on the
steric hindrance of the nitrogen of the N-nucleophile (Scheme
4).
Scheme 4. Comparison between Our Three-Component
Reaction and a Related One Starting from Primary Amines
a
b
Isolated yields, after crystallization or chromatography. Experiments
carried out with 1:2:3 ratio of chalcone:β-ketoamide:ammonium
acetate (+1 additional eq of ammonium acetate after 24 h).
c
Experiments carried out at 50 °C.
Mechanistically, both reactions are proposed to start by the
generation of an intermediate β-enaminone I via the CAN-
catalyzed reaction between the starting primary amine or
ammonia and the β-dicarbonyl compound 2. This assumption
is based on two facts: (a) CAN catalysis is known to lead to the
very fast formation of β-enaminones;34 (b) control experiments
carried out from an isolated enaminone (3-aminocrotonamide)
led to a result that was identical to that of our three-component
reactions. A Michael addition of I onto the enone fragment of
chalcones 1 should lead to intermediate II, which would be in
tautomeric equilibrium with two enamine species III and IV. In
the case R = H, the unhindered nitrogen atom is able to attack
the opposing carbonyl as a nucleophile, leading to dihydropyr-
idine V after loss of a molecule of water, in a Hantzsch-like
process. On the other hand, for the more hindered cases where
R is different from hydrogen, the reaction with the side chain
Figure 2. Additional nicotinamides bearing heterocyclic or styryl C-4
substituents.
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carbonyl is slower because of steric hindrance and the system
tends to evolve via the less stable, but also more reactive,
intermediate IV, which affords the cyclohexene derivatives VI
(Scheme 5).
mL) was added ceric ammonium nitrate (CAN, 10% mol) and
the resulting mixture was refluxed for the time given in table 2.
After completion of the reaction (checked by TLC), the
mixture was poured onto ice water (15 mL) and the precipitate
formed was collected by filtration and washed with water. In
some cases (compounds 3o−3q, 7a, 7b, and 8b), the cooled
reaction mixture was diluted with CH2Cl2 (15 mL) and washed
with water to remove CAN and the excess of ammonium
acetate. The organic layer was then washed with brine and
dried over anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The crude residue was recrystallized
from EtOH or purified by silica column chromatography,
eluting with petroleum ether- ethyl acetate or chloroform-ethyl
acetate mixtures, to give pure compounds 3, 7, or 8.
Scheme 5. Mechanistic Proposal That Accounts for the
Results Described in This Paper
2-Methyl-4,6-diphenylnicotinamide (3a): White solid;
mp 219−221 °C; 1H NMR (250 MHz, CDCl3) δ = 8.05 (dd, J
= 7.9, 1.6 Hz, 2H), 7.64−7.41 (m, 9H), 5.63 (bs, 1H), 5.40 (bs,
1H), 2.80 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 170.8, 157.4,
155.9, 147.7, 138.9, 138.3, 129.5, 129.0, 129.0, 128.9, 128.4,
127.3, 118.7, 23.1; IR (KBr) ν 3378, 3204, 1694, 1651, 1621,
1586, 1574, 1547, 1493, 1360, 778, 757, 694 cm−1; elemental
analysis calcd (%) for C19H16N2O C 79.14, H 5.59, N 9.72;
found C 78.93, H 5.53, N 9.51.
2-Methyl-6-(4-methylphenyl)-4-phenylnicotinamide
1
(3b): White solid; mp 248−250 °C; H NMR (250 MHz,
DMSO) δ = 8.06 (d, J = 7.8 Hz, 2H), 7.87 (s, 1H), 7.71 (s,
1H), 7.67−7.38 (m, 6H), 7.31 (d, J = 7.8 Hz, 2H), 2.60 (s,
3H), 2.38 (s, 3H); 13C NMR (63 MHz, DMSO) δ 169.8, 154.9,
153.9, 146.7, 138.8, 138.5, 135.5, 130.7, 129.3, 128.3, 126.7,
117.7, 22.6, 20.9; IR (KBr) ν 3380, 3204, 2913, 1692, 1651,
1620, 1584, 1546, 1359, 822, 761, 700 cm−1; elemental analysis
calcd (%) for C20H18N2O C 79.44, H 6.00, N 9.26; found C
79.24, H 5.95, N 9.30.
While dihydropyridines are normally reasonably stable,
during the optimization studies, we never observed compounds
V as the only reaction products but as part of mixtures with
pyridines 3, indicating that they are particularly prone to
oxidation. Furthermore, a control experiment with an ester (Z
= OEt) gave a stable dihydropyridine, which shows that this
ease of oxidation has to be attributed to the presence of the
amide substituent. This behavior can be attributed to the very
strong conjugation between the amide carbonyl and its
nitrogen, which makes the carbonyl less prone to accept
electron density from the dihydropyridine nitrogen and hence
makes the latter more electron-rich and the corresponding
heterocycle more readily oxidizable. In the case of compounds
7, the more rigid structure must hamper dehydrogenation by
facilitating conjugation of the dihydropyridine nitrogen with the
lactam carbonyl.
4,6-Bis(4-methylphenyl)-2-methylnicotinamide (3c):
1
White solid; mp 247−249 °C; H NMR (250 MHz, CDCl3)
δ = 7.94 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J = 8.1 Hz,
2H), 7.37−7.19 (m, J = 7.9, 3.0 Hz, 4H), 5.69 (bs, 1H), 5.44
(bs, 1H), 2.76 (s, 3H), 2.44 (s, 6H); 13C NMR (63 MHz,
CDCl3) δ 171.1, 157.2, 155.7, 147.5, 139.4, 138.9, 136.1, 135.4,
129.7, 129.6, 128.6, 128.2, 127.1, 118.3, 23.0, 21.4, 21.4; IR
(KBr) ν 3446, 3289, 3180, 1652, 1606, 1540, 1512, 1360, 1189,
825, 795, 582, 572, 542 cm−1; elemental analysis calcd (%) for
C21H20N2O C 79.72, H 6.37, N 8.85; found C 79.81, H 6.26, N
8.62.
CONCLUSIONS
■
In conclusion, the CAN-catalyzed reaction between chalcones,
β-ketoamides and ammonium acetate constitutes an excellent
route to highly substituted nicotinamides, which can be
extended to the preparation of their fused derivatives. These
compounds have a 6-aryl substituent and lack a C-5 carbonyl
function and hence are not readily accessible through
traditional Hantzsch chemistry. This three-component reaction,
which can be considered as a new application of [3 + 3] aza-
annulations35 to the generation of molecular diversity, leads to
the formation of one C−C and two C−N bonds in a single
synthetic operation and normally proceeds in good to excellent
yield in spite of involving up to five individual steps.
4-(4-Methoxyphenyl)-2-methyl-6-phenylnicotinamide
1
(3d): White solid; mp 233−235 °C; H NMR (250 MHz,
DMSO) δ = 8.14 (dd, J = 7.8, 1.5 Hz, 2H), 7.88 (s, 1H), 7.72
(s, 1H), 7.63−7.40 (m, 6H), 7.05 (d, J = 8.7 Hz, 2H), 3.82 (s,
3H), 2.59 (s, 3H); 13C NMR (63 MHz, DMSO) δ 170.0, 159.5,
154.8, 154.0, 146.3, 138.4, 130.9, 130.5, 129.7, 129.1, 128.7,
126.8, 117.9, 113.8, 55.2, 22.6; IR (KBr) ν 3373, 3195, 2840,
1682, 1652, 1644, 1608, 1586, 1574, 1515, 832, 767, 697 cm−1;
elemental analysis calcd (%) for C20H18N2O2 C 75.45, H 5.70,
N 8.80; found C 75.11, H 5.64, N 8.71.
4,6-Bis(4-methoxyphenyl)-2-methylnicotinamide (3e):
1
Pale yellow solid; mp 239−241 °C; H NMR (250 MHz,
DMSO) δ = 8.11 (d, J = 8.6 Hz, 2H), 7.84 (s, 1H), 7.65 (s,
1H), 7.58 (d, J = 8.6 Hz, 2H), 7.53 (s, 1H), 7.04 (d, J = 7.4 Hz,
4H), 3.83 (s, 3H), 3.82 (s, 3H), 2.57 (s, 3H); 13C NMR (63
MHz, DMSO) δ 170.1, 160.2, 159.5, 154.5, 153.8, 146.3, 130.8,
130.7, 130.2, 129.7, 128.1, 117.0, 114.1, 113.8, 55.2, 55.2, 22.6;
IR (KBr) ν 3363, 3188, 2970, 1836, 1683, 1644, 1607, 1513,
1463, 1361, 1296, 1260, 1175, 1032, 829 cm−1; elemental
EXPERIMENTAL PROCEDURES
■
General Procedure for the Synthesis of Nicotinamide
Derivatives. To a stirred solution of the suitable 1,3-diphenyl-
2-propen-1-one derivative (1 equiv, 1 mmol), the appropriate
primary or secondary β-ketoamide derivative (1.1 equiv, 1.1
mmol) and ammonium acetate (3 equiv, 3 mmol) in ethanol (1
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analysis calcd (%) for C21H20N2O3 C 72.40, H 5.79, N 8.04;
found C 72.11, H 5.74, N 7.90.
118.2, 22.6; IR (KBr) ν 3270, 3063, 1649, 1602, 1546, 1489,
1442, 1373, 1326, 1239, 886, 759, 693 cm−1; elemental analysis
calcd (%) for C25H20N2O C 82.39, H 5.53, N 7.69; found C
82.14, H 5.61, N 7.57.
4,6-Bis(4-chlorophenyl)-2-methylnicotinamide (3f):
1
White solid; mp 259−261 °C; H NMR (250 MHz, DMSO)
δ = 8.21 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.82 (s, 1H), 7.68−
7.51 (m, 7H), 2.61 (s, 3H); 13C NMR (63 MHz, DMSO) δ
169.4, 154.3, 153.7, 145.7, 137.0, 136.9, 134.1, 133.5, 131.2,
130.3, 128.7, 128.6, 128.4, 118.0, 22.5; IR (KBr) ν 3314, 3157,
1668, 1600, 1543, 1493, 1366, 1091, 1015, 829, 673 cm−1;
elemental analysis calcd (%) for C19H14Cl2N2O C 63.88, H
3.95, N 7.84; found C 63.54, H 3.94, N 7.88.
2-Ethyl-N,4,6-triphenylnicotinamide (3l): White solid;
1
mp 232−234 °C; H NMR (250 MHz, DMSO) δ = 10.46 (s,
1H), 8.21 (dd, J = 7.9, 1.5 Hz, 2H), 7.85 (s, 1H), 7.63 (dd, J =
7.9, 1.5 Hz, 2H), 7.58−7.36 (m, 8H), 7.28 (t, J = 7.8, 2H), 7.06
(t, J = 7.3, 1H), 2.91 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz,
3H); 13C NMR (63 MHz, DMSO) δ 166.3, 159.0, 155.6, 147.4,
138.6, 138.3, 138.1, 130.2, 129.3, 128.8, 128.8, 128.5, 128.3,
126.9, 123.9, 119.6, 118.2, 28.6, 13.7; IR (KBr) ν 3265, 3128,
3017, 2973, 1652, 1538, 1369, 1323, 1240, 1184, 1142, 1104,
1074, 758, 692, 566 cm−1; elemental analysis calcd (%) for
C26H22N2O C 82.51, H 5.86, N 7.40; found C 82.23, H 5.89, N
7.56.
6-(4-Chlorophenyl)-2-methyl-4-(2-nitrophenyl)-
1
nicotinamide (3g): Pale yellow solid; mp 228−230 °C; H
NMR (250 MHz, CDCl3) δ = 8.07 (d, J = 7.3 Hz, 1H), 7.94 (d,
J = 8.5 Hz, 2H), 7.78−7.58 (m, 2H), 7.50−7.40 (m, 3H), 7.29
(s, 1H), 6.08 (s, 1H), 5.76 (s, 1H), 2.78 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 169.6, 156.1, 155.9, 148.2, 144.5, 136.7, 135.8,
133.5, 133.1, 131.7, 129.9, 129.1, 128.9, 128.5, 124.5, 116.5,
23.0; IR (KBr) ν 3443, 3122, 1682, 1652, 1584, 1574, 1557,
1520, 1506, 1495, 1360, 1094, 840, 784, 735, 700, 531 cm−1;
elemental analysis calcd (%) for C19H14ClN3O3 C 62.05, H
3.84, N 11.43; found C 61.95, H 3.87, N 11.24.
N,4,6-Triphenyl-2-propylnicotinamide (3m): White
1
solid; mp 230−232 °C; H NMR (250 MHz, DMSO) δ =
10.42 (s, 1H), 8.20 (dd, J = 7.9, 1.4 Hz, 2H), 7.84 (s, 1H), 7.63
(dd, J = 7.9, 1.5 Hz, 2H), 7.56−7.36 (m, 8H), 7.28 (t, J = 7.8
Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 2.90−2.80 (m, 2H), 1.96−
1.76 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (63 MHz,
DMSO) δ 166.3, 157.9, 155.5, 147.4, 138.5, 138.4, 138.1, 130.5,
129.3, 128.8, 128.8, 128.5, 128.5, 128.3, 126.9, 123.9, 119.7,
118.2, 37.4, 22.2, 14.1; IR (KBr) ν 3230, 3130, 3062, 2955,
2925, 2869, 1645, 1600, 1538, 1488, 1443, 1376, 1328, 888,
765, 740, 702, 692 cm−1; elemental analysis calcd (%) for
C27H24N2O C 82.62, H 6.16, N 7.14; found C 82.36, H 6.09, N
7.00.
2-Methyl-4-(4-methylphenyl)-6-(2-nitrophenyl)-
1
nicotinamide (3h): White solid; mp 214−216 °C; H NMR
(250 MHz, DMSO) δ = 8.07−7.88 (m, 3H), 7.85−7.76 (m,
1H), 7.75−7.66 (m, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.55 (d, J
= 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.49 (s, 3H), 2.39 (s,
3H); 13C NMR (63 MHz, DMSO) δ 169.4, 154.0, 153.3, 149.2,
146.8, 138.1, 134.9, 133.5, 132.7, 131.4, 131.3, 129.9, 129.1,
128.3, 124.2, 120.3, 22.2, 20.8; IR (KBr) ν 3370, 3188, 1667,
1585, 1538, 1434, 1360, 1115, 1090, 824, 782, 753, 710 cm−1;
elemental analysis calcd (%) for C20H17N3O3 C 69.15, H 4.93,
N 12.10; found C 68.95, H 4.95, N 12.11.
2-Isopropyl-N,4,6-triphenylnicotinamide (3n): White
1
solid; mp 252−254 °C; H NMR (250 MHz, DMSO) δ =
10.44 (s, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.83 (s, 1H), 7.64 (d, J
= 6.7 Hz, 2H), 7.57−7.34 (m, 8H), 7.27 (t, J = 7.7 Hz, 2H),
7.05 (t, J = 7.1 Hz, 1H), 3.36−3.11 (m, 1H), 1.36 (d, J = 6.5,
6H); 13C NMR (63 MHz, DMSO) δ 166.3, 162.4, 155.6, 147.3,
138.5, 138.5, 138.2, 129.7, 129.3, 128.8, 128.7, 128.4, 128.3,
126.8, 123.8, 119.7, 118.2, 32.7, 22.6; IR (KBr) ν 3230, 3130,
3062, 2970, 2926, 1646, 1599, 1588, 1552, 1538, 1496, 1443,
1336, 888, 771, 758, 704, 691 cm−1; elemental analysis calcd
(%) for C27H24N2O C 82.62, H 6.16, N 7.14; found C 82.41, H
6.22, N 7.05.
2,5-Dimethyl-4,6-diphenylnicotinamide (3i): White
1
solid; mp 228−230 °C; H NMR (250 MHz, CDCl3) δ =
7.58−7.38 (m, 8H), 7.32 (dd, J = 7.5, 1.8 Hz, 2H), 5.53 (s,
1H), 5.37 (s, 1H), 2.69 (s, 3H), 2.04 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 170.4, 159.4, 151.6, 147.8, 140.7, 137.4, 130.3,
129.1, 128.7, 128.6, 128.4, 128.3, 128.2, 126.4, 22.5, 17.8; IR
(KBr) ν 3346, 3175, 3055, 2923, 1668, 1652, 1614, 1557, 1493,
1444, 1402, 1360, 751, 701 cm−1; elemental analysis calcd (%)
for C20H18N2O C 79.44, H 6.00, N 9.26; found C 79.25, H
6.07, N 9.16.
(2-Methyl-4,6-diphenylpyridin-3-ylcarbonyl)-
(piperidin-1-yl)ketone (3o): Pale yellow solid; mp 212−214
1
N-Cyclohexyl-4,6-bis(4-methylphenyl)-2-methylnico-
°C; H NMR (250 MHz, CDCl3) δ = 8.15−7.96 (m, 2H),
1
tinamide (3j): Pale yellow solid; mp 214−216 °C; H NMR
7.71−7.55 (m, 3H), 7.55−7.41 (m, 6H), 3.74−3.58 (m, 1H),
3.58−3.42 (m, 1H), 3.07−2.92 (m, 1H), 2.86−2.72 (m, 1H),
2.68 (s, 3H), 1.60−1.35 (m, 3H), 1.35−1.14 (m, 2H), 0.80−
0.58 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 167.7, 156.9,
155.3, 146.9, 139.0, 138.1, 129.1, 128.8, 128.7, 128.6, 127.1,
118.2, 47.2, 42.1, 25.8, 25.1, 24.2, 22.9; IR (KBr) ν 3438, 3058,
2940, 2858, 1628, 1586, 1545, 1494, 1443, 1369, 1272, 1237,
1000, 788, 765, 743, 701 cm−1; elemental analysis calcd (%) for
C24H24N2O C 80.87, H 6.79, N 7.86; found C 80.58, H 6.70, N
7.59.
(250 MHz, CDCl3) δ = 7.93 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H),
7.44 (d, J = 8.1 Hz, 2H), 7.37−7.18 (m, 4H), 5.25 (d, J = 8.5
Hz, 1H), 3.94−3.74 (m, 1H), 2.73 (s, 3H), 2.43 (s, 6H), 1.74−
1.47 (m, 5H), 1.41−1.21 (m, 2H), 1.17−1.03 (m, 1H), 0.97−
0.78 (m, 2H); 13C NMR (63 MHz, CDCl3) δ 167.9, 157.0,
155.9, 147.6, 139.3, 138.7, 136.3, 135.5, 129.8, 129.6, 129.4,
128.2, 127.1, 118.2, 48.2, 32.5, 25.4, 24.6, 23.0, 21.4, 21.3; IR
(KBr) ν 3230, 3062, 2922, 2851, 1620, 1325, 1260, 1186, 1151,
1113, 1020, 860, 819, 725, 712 cm−1; elemental analysis calcd
(%) for C27H30N2O C 81.37, H 7.59, N 7.03; found C 81.12, H
7.32, N 6.98.
(2-Methyl-4,6-diphenylpyridin-3-ylcarbonyl)-
(morpholin-4-yl)ketone (3p): Pale yellow solid; mp 132−
134 °C; 1H NMR (250 MHz, CDCl3) δ = 8.11−8.00 (m, 2H),
7.64 (s, 1H), 7.62−7.45 (m, 8H), 3.80−3.49 (m, 3H), 3.41−
3.22 (m, 1H), 3.17−3.01 (m, 1H), 2.91−2.75 (m, 1H), 2.70 (s,
3H), 2.68−2.56 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 168.0,
157.4, 155.6, 147.2, 138.8, 138.0, 129.4, 129.2, 129.0, 128.9,
128.6, 127.8, 127.2, 118.1, 66.3, 66.3, 46.6, 41.7, 23.0; IR (KBr)
ν 3052, 2983, 2918, 2859, 1634, 1587, 1540, 1495, 1436, 1383,
2-Methyl-N,4,6-triphenylnicotinamide (3k): Pale yellow
1
solid; mp 226−228 °C; H NMR (250 MHz, DMSO) δ =
10.50 (s, 1H), 8.20 (d, J = 6.5 Hz, 2H), 7.86 (s, 1H), 7.64 (d, J
= 6.5 Hz, 2H), 7.59−7.38 (m, 8H), 7.30 (t, J = 7.8 Hz, 3H),
7.08 (t, J = 7.2 Hz, 1H), 2.64 (s, 3H); 13C NMR (63 MHz,
DMSO) δ 166.3, 155.6, 154.5, 147.4, 138.6, 138.2, 138.0, 130.5,
129.4, 128.8, 128.7, 128.6, 128.5, 128.2, 126.9, 123.9, 119.7,
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Research Article
1366, 1302, 1277, 1260, 1238, 1113, 1008, 788 cm−1; elemental
analysis calcd (%) for C23H22N2O2 C 77.07, H 6.19, N 7.82;
found C 76.91, H 6.24, N 7.80.
7.41−7.32 (m, 5H), 6.60 (s, 1H), 5.97 (bs, 1H), 5.43 (bs, 1H),
4.10 (td, J = 8.8, 5.2, 1H), 3.62 (d, J = 8.9, 1H), 3.33 (dd, J =
18.0, 5.0, 1H), 3.06 (dd, J = 18.0, 9.0, 1H); 13C NMR (63 MHz,
CDCl3) δ 196.0, 170.9, 159.9, 142.3, 138.2, 130.9, 129.3, 129.2,
127.8, 127.6, 126.7, 124.6, 59.1, 42.8, 35.3; IR (KBr) ν 3049,
1679, 1650, 1599, 1543, 1367, 1112, 758 cm−1; elemental
analysis calcd (%) for C19H17NO2 C 78.33; H 5.88; N 4.81;
found C 78.60, H 5.96, N 4.97.
tert-Butyl 5-oxo-2,4-diphenyl-4,5,7,8-tetrahydro-1,6-
naphthyridine-6(1H)-carboxylate (7a): White solid; mp
253 °C (dec.); 1H NMR (250 MHz, DMSO) δ = 8.79 (s, 1H),
7.53−7.45 (m, 2H), 7.45−7.34 (m, 3H), 7.31−7.26 (m, 4H),
7.21−7.09 (m, 1H), 5.21 (dd, J = 5.3, 1.6 Hz, 1H), 4.63 (d, J =
5.4 Hz, 1H), 4.08−3.94 (m, 1H), 3.56−3.39 (m, 1H), 2.82−
2.57 (m, 2H), 1.42 (s, 9H); 13C NMR (63 MHz, DMSO) δ
164.6, 152.5, 149.5, 148.2, 134.9, 134.2, 128.5, 128.4, 128.2,
127.4, 125.8, 125.5, 105.1, 99.5, 80.8, 42.0, 37.9, 27.8, 26.3; IR
(KBr) ν 3324, 3058, 3022, 2975, 2930, 2879, 1748, 1656, 1620,
1504, 1402, 1369, 1310, 1217, 1158, 1130, 914, 757, 697 cm−1;
elemental analysis calcd (%) for C25H26N2O3 C 74.60, H 6.51,
N 6.96; found C 74.70, H 6.42, N 7.08.
2,4-Diphenyl-4,6,7,8-tetrahydro-1,6-naphthyridin-
5(1H)-one (7b): Pale yellow solid; mp 267−269 °C; 1H NMR
(250 MHz, DMSO) δ = 8.27 (s, 1H), 7.48 (dd, J = 8.0, 1.7 Hz,
2H), 7.42−7.31 (m, 3H), 7.25 (d, J = 4.3 Hz, 4H), 7.18−7.04
(m, 1H), 6.77 (s, 1H), 5.09 (dd, J = 5.3, 1.6 Hz, 1H), 4.61 (d, J
= 5.3 Hz, 1H), 3.29−3.09 (m, 2H), 2.59−2.50 (m, 2H); 13C
NMR (63 MHz, DMSO) δ 168.1, 148.9, 145.5, 135.5, 135.0,
128.4, 128.2, 128.1, 127.6, 127.5, 125.5, 125.4, 103.6, 99.4, 37.8,
37.45 26.3; IR (KBr) ν 3395, 3227, 3116, 2992, 2900, 1660,
1652, 1634, 1614, 1514, 1505, 1495, 1470, 1434, 1417, 1385,
1332, 1282, 1230, 1199, 1032, 757, 697 cm−1; elemental
analysis calcd (%) for C20H18N2O C 79.44, H 6.00, N 9.26;
found C 79.54, H 5.80, N 8.99.
2,4-Diphenyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one
(8b): Pale yellow solid; mp 236−238 °C; 1H NMR (250 MHz,
DMSO) δ = 8.23−8.11 (m, 2H), 8.05 (s, 1H), 7.72 (s, 1H),
7.55−7.45 (m, 3H), 7.40 (s, 5H), 3.57−3.43 (m, 2H), 3.13 (t, J
= 6.0, 2H); 13C NMR (63 MHz, DMSO) δ 163.5, 160.8, 156.6,
151.3, 139.9, 137.7, 129.8, 128.8, 128.5, 127.6, 127.1, 121.9,
121.1, 37.9, 32.7; IR (KBr) ν 2887, 1668, 1652, 1574, 1538,
1480, 14034, 1344, 1247, 1171, 1078, 824, 761, 698 cm−1;
elemental analysis calcd (%) for C20H16N2O C 79.98, H 5.37, N
9.33; found C 79.95, H 5.54, N 9.14.
(2-Methyl-4,6-diphenylpyridin-3-ylcarbonyl)(4-meth-
ylpiperazin-1-yl)ketone (3q): Yellow solid; mp 132−134 °C;
1H NMR (250 MHz, CDCl3) δ = 8.06 (dd, J = 8.0 Hz, 1.6,
2H), 7.63 (s, 1H), 7.61−7.45 (m, 8H), 3.81−3.52 (m, 2H),
3.22−3.01 (m, 1H), 2.91−2.75 (m, 1H), 2.69 (s, 3H), 2.49−
2.32 (m, 1H), 2.15 (s, 3H), 2.19−1.99 (m, 2H), 1.52−1.37 (m,
1H); 13C NMR (63 MHz, CDCl3) δ 167.9, 157.2, 155.5, 147.1,
139.0, 138.1, 129.3, 129.0, 128.9 (two signals), 128.7, 128.2,
127.1, 118.1, 54.5, 54.2, 46.0, 45.9, 41.1, 23.0; IR (KBr) ν 3445,
3052, 2997, 2938, 2844, 2796, 1620, 1574, 1541, 1441, 1294,
1271, 1018, 999, 760, 700 cm−1; elemental analysis calcd (%)
for C24H25N3O C 77.60, H 6.78, N 11.31; found C 77.44, H
6.67, N 11.02.
2-Methyl-6-phenyl-4-(thiophen-2-yl)nicotinamide
1
(3r): Pale yellow solid, mp 199−201 °C; H NMR (250 MHz,
CDCl3) δ = 8.03 (dd, J = 8.0, 1.7 Hz, 2H), 7.68 (s, 1H), 7.58−
7.42 (m, 5H), 7.16 (dd, J = 5.1, 3.7 Hz, 1H), 5.86 (bs, 1H),
5.71 (bs, 1H), 2.77 (s, 3H); 13C NMR (63 MHz, CDCl3) δ
171.1, 157.5, 155.8, 139.9, 138.9, 138.6, 129.5, 128.9, 128.5,
128.3, 128.0, 127.8, 127.2, 118.1, 22.9; IR (KBr) ν 3310, 3140,
1652, 1591, 1495, 1433, 1376, 1242, 1094, 856, 767, 677, 622
cm−1; elemental analysis calcd (%) for C17H14N2OS C 69.36, H
4.79, N 9.52, S 10.89; found C 68.99, H 4.92, N 9.42, S 10.85.
2-Methyl-6-(4-methylphenyl)-4-(thiophen-2-yl)-
1
nicotinamide (3s): Pale yellow solid; mp 206−208 °C; H
NMR (250 MHz, CDCl3) δ = 7.94 (d, J = 8.2 Hz, 2H), 7.65 (s,
1H), 7.53 (dd, J = 3.6, 0.9 Hz, 1H), 7.48 (dd, J = 5.1, 0.9 Hz,
1H), 7.32 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 5.1, 3.6 Hz, 1H),
5.79 (s, 1H), 5.73 (s, 1H), 2.76 (s, 3H), 2.45 (s, 3H); 13C NMR
(63 MHz, CDCl3) δ 171.1, 157.5, 155.7, 139.9, 139.7, 139.0,
135.8, 129.6, 128.5, 128.2, 127.7, 127.1, 117.8, 22.9, 21.4; IR
(KBr) ν 3438, 3278, 3169, 1651, 1545, 1513, 1431, 1357, 829,
703, 556, 538 cm−1; elemental analysis calcd (%) for
C18H16N2OS C 70.10, H 5.23, N 9.08, S 10.40; found C
69.88, H 5.30, N 8.98, S 10.33.
2-Methyl-6-phenyl-4-styrylnicotinamide (3t): Pale yel-
low solid; mp 199−201 °C; 1H NMR (250 MHz, DMSO) δ =
8.27−8.09 (m, 4H), 7.91−7.72 (m, 2H), 7.66−7.32 (m, 8H),
7.15 (d, J = 16.3 Hz, 1H), 2.56 (s, 3H); 13C NMR (63 MHz,
DMSO) δ 169.7, 154.8, 154.0, 141.6, 138.5, 136.3, 134.2, 130.9,
129.1, 129.0, 128.8, 128.7, 126.9, 126.8, 123.4, 112.6, 22.5; IR
(KBr) ν 3380, 3180, 1640, 1576, 1540, 1496, 1448, 1385, 1269,
1217, 1121, 958, 767, 690 cm−1; elemental analysis calcd (%)
for C21H18N2O C 80.23, H 5.77, N 8.91; found C 79.90, H
5.79, N 8.82.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
2-Methyl-6-phenyl-4-(1-phenylprop-1-en-2-yl)-
1
nicotinamide (3u): White solid, mp 186−188 °C; H NMR
(250 MHz, DMSO) δ = 8.14 (dd, J = 8.0, 1.5 Hz, 2H), 7.92 (s,
1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.57−7.23 (m, 8H), 6.65 (s,
1H), 2.59 (s, 3H), 2.25 (d, J = 1.2 Hz, 3H); 13C NMR (63
MHz, DMSO) δ 169.9, 154.6, 154.0, 150.9, 138.3, 137.0, 135.4,
130.5, 129.8, 129.1, 128.9, 128.7, 128.3, 127.0, 126.7, 116.4,
22.7, 18.7; IR (KBr) ν 3398, 3312, 3201, 3059, 1689, 1651,
1620, 1586, 1576, 1537, 1358, 1154, 1076, 1005, 755, 700
cm−1; elemental analysis calcd (%) for C22H20N2O C 80.46, H
6.14, N 8.53; found C 80.14, H 6.07, N 8.65.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail josecm@farm.ucm.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-Oxo-4,6-Diphenylcyclohex-3-enecarboxamide (5)
We thank Javier Blazquez for some experimental assistance.
́
from Robinson Annelation: Pale yellow solid; mp 175−
Financial support from MICINN (grant CTQ2009-12320-
BQU) and Universidad Complutense (grant GR35/10-A-
920234 and fellowship to G.T.) is also gratefully acknowledged.
1
1
177 °C; H NMR (250 MHz, CDCl3) H NMR (250 MHz,
CDCl3) δ = 7.59 (dd, J = 6.7, 3.0, 2H), 7.52 − 7.42 (m, 3H),
556
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(21) Attar, S.; O’Brien, Z.; Alhaddad, H.; Golden, M. L.; Calderon-
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