Pyridin-2-one synthesis using ester enolates and aryl aminoaldehydes and ketones

Article abstract of DOI:10.1021/jo500284n

An aldol-like cyclocondensation has been used to prepare heterocyclic-fused pyridin-2-ones from aminoaldehydes and ketones upon treatment with a lithium enolate of ethyl acetate or α-substituted acetates. These motifs are present in a large number of biologically active natural products and synthetic compounds and can be accessed using mild reaction conditions using readily available starting materials. This methodology allows access to pyrimidinopyridin-2-ones, pyrazolopyridin-2-ones, and pyridopyridazine diones with varying substitution patterns.

Full text of DOI:10.1021/jo500284n

Note
pubs.acs.org/joc
Pyridin-2-one Synthesis Using Ester Enolates and Aryl
Aminoaldehydes and Ketones
Tushar Apsunde† and Ryan P. Wurz*,‡
†Department of Chemistry, University of New Orleans, 2000 Lakeshore Drive, New Orleans, Louisiana 70148, United States
‡Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States
S
* Supporting Information
ABSTRACT: An aldol-like cyclocondensation has been used to prepare
heterocyclic-fused pyridin-2-ones from aminoaldehydes and ketones upon
treatment with a lithium enolate of ethyl acetate or α-substituted acetates.
These motifs are present in a large number of biologically active natural
products and synthetic compounds and can be accessed using mild reaction
conditions using readily available starting materials. This methodology
allows access to pyrimidinopyridin-2-ones, pyrazolopyridin-2-ones, and
pyridopyridazine diones with varying substitution patterns.
a
Scheme 1. Common Routes To Access Pyridin-2-ones
he pyridin-2-one motif is present in a large number of
1
Tnaturally occurring and bioactive molecules. It can serve
as a more polar replacement for a benzene ring and help
modulate the properties of medicinally important molecules. As
such, this motif has been incorporated into a large number of
drug discovery programs targeting biochemical pathways
associated with inflammatory disorders (p38, 1−2)2 and
oncology (CDK4 33 and FGFR inhibitors 4,4 Figure 1) to
highlight a few.
a
Conditions: (a) Ph3PCHCO2Et, THF, reflux; (b) DBU, i-Pr2NEt,
160 °C; (c) Ac2O, DMF, 140 °C; (d) ArBr(I), CuI, ligand, DMSO,
130 °C; (e) ArB(OH)2, CuI, ligand, dioxane, 110 °C.
with boronic acids (condition e).8 These methods are generally
high yielding when R = alkyl, but far fewer examples exist for R
= aryl and are much lower yielding.9 A number of recent
reports have focused on the preparation of the pyridinone motif
with more limited substitution patterns. These examples
include the synthesis of naphthyridones,10 3,4-dihydroquino-
line-2(1H)-ones,11 isoquinolin-1-(2H)-ones,12 benzofuro[3,2-
b]pyridines,13 substituted cyclopentyl-fused pyridinones,14 and
pyrimidinopyridinones via ring expansions of isatins with diazo
compounds.15
As part of one of our discovery programs, we sought a mild
and scalable method to access compounds structurally related
to compound 3. Our primary focus was on the ability to access
compounds containing N-aryl substitution on the pyridinone
ring. In addition, we were interested in developing a versatile
method which would allow exploration of various substitution
patterns in other positions of the pyridinone ring. Attempted
application of known literature methods described above for
the synthesis of 7 resulted in low yields of the desired product.
Failure of these approaches was due, in part, to the thermal
lability of the Boc-protected aniline present in 5a and the
elevated reaction temperatures required for the incorporation
of the pyridinone motif.
Figure 1. Pyridin-2-one containing compounds of medicinal interest.
Depending on the nature of the substitution on the
pyridinone nitrogen, the synthesis of fused heterocyclic
pyridin-2-ones such as 3 typically involves reaction sequences
including (1) olefination of an aminoaldehyde followed by
DBU-mediated cyclization (Scheme 1, conditions a,b),5 (2)
treatment of an aminoaldehyde with Ac2O in DMF (condition
c),6 (3) Cu-catalyzed arylation of pyridin-2-(1H)-ones with aryl
halides (condition d),7 (4) metal-catalyzed coupling reactions
Received: February 5, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Note
We then turned to a milder approach using a lithium enolate
of EtOAc15,16 as a method of introducing the requisite 2-carbon
fragment to transform the aminoaldehyde 5a to the desired
pyridin-2-one 7a. In this approach, addition of the enolate to
the aldehyde would then be followed by cyclization and
aromatization of intermediate 6 to provide 7a (Scheme 2).
acidic N−H hydrogens present on the substrate. Other bases
including NaHMDS, LDA, and LiOt-Bu were also briefly
examined and produced the desired product 7a but with lower
conversions after 2 h.18 Variation of the equivalents of enolate
had little influence on the outcome of the reaction as 1.2 or 3.2
equiv of EtOAc gave essentially the same conversions as 2.2
equiv (entries 7 and 8 vs entry 1). This reaction was also
conducted in three other polar aprotic solvents and found to
give inferior conversions after 2 h reaction time presumably due
to reduced solubility of the substrate in these solvents (entries
9−11).
Scheme 2. Proposed Pyridin-2-one Synthesis
We then examined the scope of the reaction to determine the
applicability of the present set of reaction conditions to the
synthesis of structurally related N-arylpyrimidinoaldehyde and
ketone substrates (5a−e). Replacement of R1 = NHBoc with R1
= NHMe gave modest yields of the desired product 7b (Table
2, entry 2). The cyclization also performed well with a ketone
Table 2. Substrate Scope: N-Arylpyridin-2-one Analogues
Investigation of a number of reaction conditions focused
initially on EtOAc as the source of the enolate. These reaction
parameters included the identity and equivalents of base used
along with a number of polar aprotic solvents. Formation of a
lithium enolate by slow addition of EtOAc to a THF solution of
LiHMDS at −78 °C followed by stirring for 20 min was found
to be sufficient for enolate formation. The aminoaldehyde
substrate 5a was then added to the enolate solution as a solid in
one portion, and the reaction mixture was allowed to warm to
ambient temperature and stirred 2 h. This protocol provided
excellent yields of the desired pyrimidinopyridin-2-one 7a. It is
noteworthy to mention that, in the presence of 3 equiv of
LiHMDS, intermediate 6 slowly cyclizes and aromatizes during
the duration of the reaction.17 Further investigation indicated
that fewer equivalents of LiHMDS (Table 1, entries 2 and 3 vs
entry 1) resulted in significant erosion in the LC conversion of
the reaction presumably due to quenching of the enolate by the
a
entry
R
R1
product
yield (%)
1
2
3
4
5
H
NHBoc
NHMe
NHBoc
OMe
7a
7b
7c
7d
7e
85
72
78
H
Me
Me
Me
b
52
cd
,
Br
35
a
b
c
Yield of purified product. 2.2 equiv of LiHMDS was used. 2.5 equiv
d
of LiHMDS was used. The reaction time was extended to 4 h.
(5c, R = Me, entry 3).19 Reduced yields were observed when R1
= OMe or Br (entries 4 and 5). In an attempt to improve the
yield of 7e, 5 equiv of LiHMDS and EtOAc was used, resulting
in little deviation from the original result.20
Gratifyingly, good yields of 6-substituted pyridinones were
possible with a variety of α-aryl-substituted esters (Table 3,
entries 1−5).21,22 A significant decrease in yield was observed
with the less acidic β-arylated substrate presumably due to
slower rates of enolate formation under the standard reaction
conditions (entry 6).
Table 1. Optimization of Reaction Conditions
To further demonstrate the utility of the pyridinone
synthesis, substrates bearing N-methyl substitution (9a−e)
were also submitted to the reaction conditions. Modest to
excellent yields could be obtained using either an aldehyde
(Table 4, entry 1) or a variety of ketones (entries 2−5). In
these cases, 2 equiv of LiHMDS was sufficient to promote the
cyclization.
Finally, aminoaldehydes and ketones fused to other hetero-
cycles were submitted to the standard reaction conditions and
found to furnish the desired pyridinones. Accordingly,
pyrazolopyridinones (Table 5, entry 1), pyridopyridazine
diones (entry 2), and chloropyrimidinopyridinones (entry 3)
could be prepared in modest yields.
a
entry
variation from the “standard” conditions
% conversion
b
1
2
none
85 (84.5%)
LiHMDS (2 equiv)
LiHMDS (1 equiv)
NaHMDS (3 equiv)
LDA (3 equiv)
LiOt-Bu (3 equiv)
EtOAc (3.2 equiv)
EtOAc (1.2 equiv)
2-MeTHF
53
26
12
29
6
3
4
5
6
7
85
82
72
55
20
8
9
10
11
1,4-dioxane
If desired, the 5,6-disubstitution pattern can also be accessed
by use of the combination of aminoketones and α-substituted
esters as reaction partners. In this particular case, the
hydroxylated intermediate was found to be stable and could
Et2O
a
b
Percent conversion determined by LC-MS. Number in parentheses
corresponds to an isolated yield.
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Note
Table 3. Substrate Scope: 6-Substituted N-Arylpyridinone
Analogues
Table 5. Substrate Scope: Application to Other Fused
Heterocyclic Pyridinone Analogues
a
Yield of purified product.
Table 4. Substrate Scope: N-Methylpyridinone Analogues
a
b
Yield of purified product. LiHMDS (3 equiv), 2 days reaction time.
c
LiHMDS (2.5 equiv), 5 h reaction time.
a
entry
R
product
yield (%)
1
2
3
4
5
H
10a
10b
10c
l0d
l0e
85
85
67
82
Me
In conclusion, we have described an alternative synthesis of
pyridin-2-ones using an aldol-like cyclocondensation that
proceeds under mild reaction conditions. The methodology
uses readily available starting materials, furnishing modest to
excellent yields for a range of 5-, 6-, and 5,6-disubstituted
heterocyclic-fused pyridin-2-one products. It provides facile
access to N-arylated pyridin-2-ones which are challenging to
prepare using previously reported methodologies. Furthermore,
this methodology does not require the use of heavy metals (e.g.,
Pd, Cu) nor does it produce byproducts such as triphenyl-
phosphine oxide which may complicate purifications.
Ph
Bn
b
c-C5H9
50
a
b
Yield of purified product. The reaction time was 4 h.
be dehydrated to product upon addition of Martin sulfurane (1
equiv) to the reaction mixture, thereby generating the 5,6-
disubstituted pyridin-2-one 13 in a one-pot reaction (eq 1).23
EXPERIMENTAL SECTION
■
General Procedures. All reactions were run under an atmosphere
of nitrogen, with exclusion of moisture from reagents and glassware,
using standard techniques for manipulating air-sensitive compounds,
unless otherwise stated. Anhydrous tetrahydrofuran, 2-methyltetra-
hydrofuran, and 1,4-dioxane were purchased and used directly without
further manipulation. Reagents were purchased and used without
further purification. Yields refer to chromatographically and spectro-
scopically (1H NMR) homogeneous material, unless otherwise stated.
Reactions were monitored by LC-MS analysis. Flash chromatography
was performed using automated instrumentation using prepacked silica
columns. NMR spectra were recorded at 400 MHz, calibrated using
the resonance of residual protio solvents (e.g., CDCl3 at 7.27 ppm,
DMSO-d6 at 2.50 ppm) and were reported in parts per million as
follows: chemical shift (multiplicity, coupling constant (Hz),
integration). The following abbreviations were used to explain
This methodology has also been found to be useful in the
preparation of pyridinones with radiolabels24 or deuterium. Use
of EtOAc-d8 resulted in 74% isolated yield of the desired
product 14 with 92% deuterium incorporation in the 6-position
(eq 2). This observed slight erosion in deuterium content
maybe related to quenching of the enolate by the acidic N−H
protons and subsequent regeneration of the mixed D/H
containing enolate with the remaining equivalent of
LiHMDS.25
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Note
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad, dd = doublet of doublets, dt = doublet of
triplets. Melting points are given as ranges, are uncorrected, and are
reported in °C. High-resolution mass spectral analysis was acquired
using a QTOF operated in positive ion mode. IR data (υmax) are
reported in cm−1 and were collected on a FTIR spectrophotometer.
Thin films were prepared by evaporation of solutions of the compound
in dichloromethane.
tert-Butyl (3-(5-Methyl-2-(methylthio)-7-oxopyrido[2,3-d]-
pyrimidin-8(7H)-yl)phenyl)carbamate (7c). The title compound was
prepared according to the standard procedure affording the title
compound as an off-white solid (4.29 g, 78%) after suspension of the
crude material in Et2O followed by filtration of the resulting solid and
washing with additional Et2O: mp 213−216 °C; 1H NMR (400 MHz,
DMSO-d6) δ ppm 9.53 (1 H, s), 8.98 (1 H, s), 7.42−7.48 (2 H, m),
7.35−7.42 (1 H, m), 6.88 (1 H, d, J = 7.6 Hz), 6.55−6.60 (1 H, m),
2.21 (3 H, s), 1.47 (9 H, s); note one Me signal under DMSO signal;
13C NMR (101 MHz, DMSO-d6) δ ppm 171.5, 161.6, 155.0, 154.7,
152.7, 146.4, 140.2, 136.0, 129.0, 122.5, 120.4, 118.2, 117.8, 109.9,
79.3, 28.1, 17.0, 13.4; HRMS (ESI) calcd for C20H22N4O3S [M + 1]+
m/z 399.1492, found 399.1493; IR (film, cm−1) 3290, 2977, 2928,
2361, 2361, 2338, 1667, 1570, 1523, 1523, 1159.
8-(3-Methoxyphenyl)-5-methyl-2-(methylthio)pyrido[2,3-d]-
pyrimidin-7(8H)-one (7d). The title compound was prepared
according to the standard procedure, except only 2.0 equiv of
LiHMDS was used, affording the title compound as a white crystalline
solid (140 mg, 52%) following chromatography using a gradient of 0−
10% EtOAc in DCM: mp 177−179 °C; 1H NMR (400 MHz, DMSO-
d6) δ ppm 8.96 (1 H, s), 7.43 (1 H, t, J = 8.1 Hz), 7.04 (1 H, d, J = 8.4
Hz), 6.90 (1 H, br s), 6.85 (1 H, d, J = 7.4 Hz), 6.56 (1 H, s), 3.77 (3
H, s), 2.50 (3 H, s), 2.19 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ
ppm 171.4, 161.6, 159.7, 154.9, 154.8, 146.3, 136.9, 129.5, 121.1,
120.5, 114.7, 114.0, 109.9, 55.4, 17.0, 13.4; HRMS (ESI) calcd for
C16H15N3O2S [M + 1]+ m/z 314.0964, found 314.0957; IR (film,
cm−1) 3290, 2977, 2925, 2835, 2361, 2338, 1668, 1568, 1522, 1431,
1352, 1260.
tert-Butyl (3-((5-Formyl-2-(methylthio)pyrimidin-4-yl)amino)-
phenyl)carbamate (5a). This compound was prepared according to
a previously reported literature method, affording the title compound
as an off-white crystalline solid:26 mp 140−148 °C; H NMR (400
1
MHz, DMSO-d6) δ ppm 10.51 (1 H, s), 9.85 (1 H, s), 9.45 (1 H, s),
8.72 (1 H, s), 7.94 (1 H, s), 7.36 (1 H, dd, J = 8.1, 1.1 Hz), 7.26 (1 H,
t, J = 8.1 Hz), 7.10−7.19 (1 H, m), 2.53 (3 H, s), 1.48 (9 H, s); 13C
NMR (101 MHz, DMSO-d6) δ ppm 192.7, 176.7, 163.9, 156.4, 152.7,
140.1, 137.4, 129.0, 115.6, 114.6, 111.4, 109.3, 79.2, 28.1, 13.9; HRMS
(ESI) calcd for C17H20N4O3S [M + 1]+ m/z 361.1335, found
361.1335; IR (film, cm−1) 3287, 2978, 2929, 2361, 2338, 1724, 1653,
1589, 1566, 1369, 1234, 1158, 1125.
4-((3-(Methylamino)phenyl)amino)-2-(methylthio)pyrimidine-5-
carbaldehyde (5b). This compound was prepared according to a
similar procedure used for 5a, except the LiAlH4 reduction was
allowed to stir and warm to room temperature overnight, affording the
title compound as a yellow-orange solid (304 mg, 28%): mp 129−147
°C; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.46 (1 H, s), 9.78−9.88
(1 H, m), 8.64−8.74 (1 H, m), 7.09 (1 H, t, J = 8.0 Hz), 6.94 (1 H, s),
6.86 (1 H, d, J = 7.8 Hz), 6.37 (1 H, d, J = 7.8 Hz), 5.78 (1 H, d, J =
4.1 Hz), 2.64−2.75 (3 H, s), 2.53−2.60 (3 H, s); 13C NMR (101
MHz, DMSO-d6) δ ppm 192.7, 176.6, 164.0, 156.3, 150.5, 137.9,
129.2, 109.3, 108.9, 108.7, 104.3, 29.7, 28.1, 14.0; HRMS (ESI) calcd
for C13H14N4OS [M + 1]+ m/z 275.0966, found 275.0967; IR (film,
cm−1) 3395, 2361, 2338, 1653, 1590, 1566, 1372, 1125.
General Procedure for the Aldol-like Condensation and
Cyclization Reaction. LiHMDS (1.0 M in THF, 0.83 mL, 0.83
mmol) was added to THF (2.7 mL), cooled to −78 °C, and treated
with ethyl acetate (0.06 mL, 0.61 mmol) slowly dropwise. The
solution was stirred at −78 °C for 25 min, then solid tert-butyl (3-((5-
formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (5a,
100 mg, 0.277 mmol) was added in one portion, and the solution
was removed from the cooling bath and allowed to warm to room
temperature. After 2 h, the reaction was quenched with a saturated
solution of NH4Cl and extracted with EtOAc (2 × 15 mL), dried over
MgSO4, filtered, and concentrated. The reaction was purified on silica
gel (25 g column, using a gradient of 0−80% EtOAc in hexanes)
affording tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-
8(7H)-yl)phenyl)carbamate (7a, 91 mg, 0.24 mmol, 85% yield) as a
pale yellow crystalline solid.
8-(3-Bromophenyl)-5-methyl-2-(methylthio)pyrido[2,3-d]-
pyrimidin-7(8H)-one (7e). The title compound was prepared
according to the standard procedure, except that 2.5 equiv of
LiHMDS was used and the reaction time was extended to 4 h,
affording the title compound as an off-white solid (750 mg, 35%)
following purification by chromatography (using a gradient of 0−20%
1
EtOAc in dichloromethane): mp 206−214 °C; H NMR (400 MHz,
chloroform-d) δ ppm 8.74 (1 H, s), 7.57−7.64 (1 H, m), 7.42−7.46 (1
H, m), 7.37−7.42 (1 H, m), 7.17−7.23 (1 H, m), 6.56 (1 H, d, J = 1.2
Hz), 2.51 (3 H, d, J = 1.2 Hz), 2.19 (3 H, s); 13C NMR (101 MHz,
DMSO-d6) δ ppm 171.5, 161.5, 155.0, 154.7, 146.5, 137.2, 132.0,
131.2, 130.7, 128.4, 121.1, 120.4, 110.0, 17.0, 13.4; HRMS (ESI) calcd
for C15H12BrN3OS [M + 1]+ m/z 361.9963, found 361.9962; IR (film,
cm−1) 3056, 2925, 2361, 2337, 1665, 1567, 1437, 1363, 1175.
tert-Butyl (3-(6-Methoxy-2-(methylthio)-7-oxopyrido[2,3-d]-
pyrimidin-8(7H)-yl)phenyl)carbamate (8a). The title compound
was prepared according to the standard procedure, affording the title
compound as a white solid (1.70 g, 74%) following isolation by
filtration of the quenched reaction mixture and washing the resulting
solid with Et2O: mp 227−233 °C; 1H NMR (400 MHz, DMSO-d6) δ
ppm 9.56 (1 H, br s), 8.86 (1 H, br s), 7.28−7.58 (4 H, m), 6.92 (1 H,
d, J = 6.7 Hz), 3.89 (3 H, br s), 2.20 (3 H, br s), 1.47 (9 H, br s); 13C
NMR (101 MHz, DMSO-d6) δ ppm 167.8, 157.9, 155.1, 152.7, 151.2,
148.3, 140.3, 136.0, 129.1, 122.4, 118.0, 109.7, 107.2, 79.3, 56.1, 28.1,
13.4; HRMS (ESI) calcd for C20H22N4O4S [M + 1]+ m/z 415.1441,
found 415.1437; IR (film, cm−1) 3280, 3087, 2979, 2932, 2361, 2338,
1670, 1579, 1535, 1430,1165.
tert-Butyl (3-(2-(Methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-
yl)phenyl)carbamate (7a). The title compound was prepared
according to the standard procedure affording the title compound as
1
an off-white solid (91 mg, 85%): mp 225−229 °C; H NMR (400
MHz, chloroform-d) δ ppm 8.66 (1 H, s), 7.70 (1 H, d, J = 9.4 Hz),
7.52 (1 H, br s), 7.43 (1 H, t, J = 8.0 Hz), 7.27−7.32 (1 H, m), 6.93 (1
H, dt, J = 7.8, 0.9 Hz), 6.74 (1 H, d, J = 9.6 Hz), 6.66 (1 H, s), 2.19 (3
H, s), 1.50 (9 H, s); 13C NMR (101 MHz, chloroform-d) δ ppm 173.5,
162.8, 156.0, 155.3, 152.5, 139.6, 136.1, 136.0, 129.6, 123.0, 122.4,
118.5, 109.2, 81.0, 77.4, 77.3, 77.0, 76.7, 28.3, 14.1; HRMS (ESI) calcd
for C19H20N4O3S [M + 1]+ m/z 385.1335, found 385.1335; IR (film,
cm−1) 3292, 2978, 2928, 2361, 2337, 1668, 1571, 1522, 1154.
tert-Butyl (3-(2-(Methylthio)-7-oxo-6-phenylpyrido[2,3-d]-
pyrimidin-8(7H)-yl)phenyl)carbamate (8b). The title compound
was prepared according to the standard procedure, affording the title
compound (255 mg, 81%) as a pale yellow solid after suspension of
1
the crude product in Et2O and filtration: mp 244−246 °C; H NMR
8-(3-(Methylamino)phenyl)-2-(methylthio)pyrido[2,3-d]-
pyrimidin-7(8H)-one (7b). The title compound was prepared
according to the standard procedure affording the title compound as
a yellow solid (161 mg, 72%): mp 134−164 °C; 1H NMR (400 MHz,
DMSO-d6) δ ppm 8.92 (1 H, s), 8.01 (1 H, d, J = 9.2 Hz), 7.22 (1 H, t,
J = 7.6 Hz), 6.68 (1 H, d, J = 9.4 Hz), 6.63 (1 H, d, J = 7.8 Hz), 6.33−
6.50 (2 H, m), 5.68−5.88 (1 H, m), 2.68 (3 H, br s), 2.24 (3 H, s); 13C
NMR (101 MHz, DMSO-d6) δ ppm 171.5, 162.0, 156.9, 154.9, 150.7,
136.8, 136.5, 129.2, 121.9, 115.5, 111.6, 109.4, 29.8, 13.5; HRMS
(ESI) calcd for C15H14N4OS [M + 1]+ m/z 299.0967, found 299.0967.
(400 MHz, DMSO-d6) δ ppm 9.54 (1 H, br s), 8.96 (1 H, br s), 8.22
(1 H, br s), 7.62−7.79 (2 H, m), 7.54 (1 H, br s), 7.42 (5 H, br s),
6.96 (1 H, br s), 2.22 (3 H, br s), 1.45 (9 H, br s); 13C NMR (101
MHz, DMSO-d6) δ ppm 171.2, 161.4, 157.2, 154.2, 152.7, 140.3,
136.4, 135.5, 134.3, 131.7, 129.0, 128.8, 128.4, 128.1, 122.5, 118.2,
118.0, 109.8, 79.3, 28.1, 13.5; HRMS (ESI) calcd for C25H24N4O3S [M
+ 1]+ m/z 461.1648, found 461.1653; IR (film, cm−1) 3286, 2979,
2926, 2362, 2337, 1609, 1572, 1531, 1433, 1160.
tert-Butyl (3-(6-(4-Chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3-
d]pyrimidin-8(7H)-yl)phenyl)carbamate (8c). The title compound
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Note
was prepared according to the standard procedure, affording the title
procedure. The crude material was suspended in Et2O and filtered
using a medium porosity sintered glass frit and washed with Et2O,
affording the title compound (1.45 g, 85%) as a tan solid: mp 181−195
°C; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1 H, s), 6.46−6.53
(1 H, s), 3.56 (3 H, s), 2.61 (3 H, s), 2.40−2.47 (3 H, s); 13C NMR
(101 MHz, DMSO-d6) δ ppm 171.8, 161.9, 154.8, 154.0, 145.4, 119.9,
110.0, 27.2, 16.8, 13.8; HRMS (ESI) calcd for C10H11N3OS [M + 1]+
m/z 222.0702, found 222.0701; IR (film, cm−1) 3041, 2927, 2361,
2337, 1657, 1572, 1451, 1372, 1194.
8-Methyl-2-(methylthio)-5-phenylpyrido[2,3-d]pyrimidin-7(8H)-
one (10c). The title compound was prepared according to the
standard procedure. The crude material was chromatographed (using a
gradient of 0−80% EtOAc in hexanes), affording the title compound
(184 mg, 67%) as a light yellow solid: mp 119−135 °C; 1H NMR (400
MHz, DMSO-d6) δ ppm 8.51 (1 H, s), 7.49−7.61 (6 H, m), 6.55 (1 H,
s), 2.61 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 172.0,
161.6, 155.5, 154.4, 147.9, 134.1, 129.5, 129.0, 128.8, 119.9, 108.9,
27.5, 13.9; HRMS (ESI) calcd for C15H13N3OS [M + 1]+ m/z
284.0858, found 284.0862; IR (film, cm−1) 3057, 2927, 2361, 2337,
1665, 1597, 1565, 1520, 1352, 1203.
5-Benzyl-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-
one (10d). The title compound was prepared according to the
standard procedure. The crude material was chromatographed (using a
gradient of 0−80% EtOAc in hexanes), affording the title compound
(223 mg, 82%) as a pale yellow solid: mp 178−180 °C; 1H NMR (400
MHz, DMSO-d6) δ ppm 8.95 (1 H, s), 7.28−7.36 (4 H, m), 7.19−7.28
(1 H, m), 6.41 (1 H, s), 4.23 (2 H, s), 3.56 (3 H, s), 2.58 (3 H, s); 13C
NMR (101 MHz, DMSO-d6) δ ppm 171.7, 161.9, 154.8, 154.3, 147.8,
137.7, 128.9, 128.7, 126.7, 120.3, 109.1, 35.7, 27.3, 13.8; HRMS (ESI)
calcd for C16H15N3OS [M + 1]+ m/z 298.1015, found 298.1011; IR
(film, cm−1) 3028, 2926, 2362, 2337, 1664, 1567, 1525, 1454, 1360,
1183.
5-Cyclopentyl-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-
7(8H)-one (10e). The title compound was prepared according to the
standard procedure. The crude material was chromatographed (using a
gradient of 0−80% EtOAc in hexanes), affording the title compound
(136 mg, 50%) as an off-white solid: mp 141−145 °C; 1H NMR (400
MHz, DMSO-d6) δ ppm 9.03 (1 H, s), 6.45 (1 H, s), 3.56 (3 H, s),
3.44−3.54 (1 H, m), 2.60 (3 H, s), 1.99−2.15 (2 H, m), 1.72 (4 H, d, J
= 6.8 Hz), 1.51−1.65 (2 H, m); 13C NMR (101 MHz, DMSO-d6) δ
ppm 171.5, 162.1, 154.6, 154.2, 152.5, 115.7, 109.5, 31.9, 27.3, 24.9,
13.8; HRMS (ESI) calcd for C14H17N3OS [M + 1]+ m/z 276.1171,
found 276.1170; IR (film, cm−1) 3459, 2946, 2920, 2866, 2361, 2336,
1653, 1566, 1522, 1448, 1363, 1188.
compound (316 mg, 92%) as a pale yellow solid after suspension of
1
the crude product in Et2O and filtration: mp 225−231 °C; H NMR
(400 MHz, DMSO-d6) δ ppm 9.55 (1 H, s), 8.98 (1 H, s), 8.28 (1 H,
s), 7.76 (2 H, d, J = 8.4 Hz), 7.49−7.60 (3 H, m), 7.35−7.48 (2 H, m),
7.05 (1 H, br s), 6.96 (1 H, d, J = 6.5 Hz), 2.23 (3 H, s), 1.46 (9 H, s);
13C NMR (101 MHz, DMSO-d6) δ ppm 171.4, 161.3, 157.3, 154.2,
152.7, 140.3, 136.3, 134.6, 134.3, 133.1, 130.5, 130.3, 129.0, 128.1,
122.5, 118.1, 109.7, 79.3, 67.0, 28.1, 25.1, 13.5; HRMS (ESI) calcd for
C25H23ClN4O3S [M + 1]+ m/z 495.1258, found 495.1255; IR (film,
cm−1) 3284, 3064, 2981, 2926, 2361, 2337, 1708, 1650, 1574, 1244,
1160.
tert-Butyl (3-(6-(4-Methoxyphenyl)-2-(methylthio)-7-oxopyrido-
[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8d). The title com-
pound was prepared according to the standard procedure, affording
the title compound (275 mg, 81%) as a pale yellow solid after
suspension of the crude product in Et2O and filtration: mp 214−218
°C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (1 H, br s), 8.95 (1
H, br s), 8.17 (1 H, br s), 7.62−7.79 (2 H, m), 7.55 (1 H, br s), 7.45
(2 H, br s), 6.83−7.09 (3 H, m), 3.81 (3 H, br s), 2.23 (3 H, br s),
1.47 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 170.7, 161.5,
159.4, 156.9, 153.9, 152.7, 140.3, 136.5, 132.9, 131.2, 130.0, 129.0,
127.7, 122.5, 118.2, 117.9, 113.5, 109.9, 79.3, 55.2, 38.9, 28.1, 13.5;
HRMS (ESI) calcd for C26H26N4O4S [M + 1]+ m/z 491.1754, found
491.1755; IR (film, cm−1) 3277, 3077, 2977, 2930, 2361, 2337, 1705,
1652, 1571, 1243, 1158.
tert-Butyl (3-(2-(Methylthio)-7-oxo-6-(thiophen-3-yl)pyrido[2,3-
d]pyrimidin-8(7H)-yl)phenyl)carbamate (8e). The title compound
was prepared according to the standard procedure, affording the title
compound (240 mg, 76%) as a pale yellow solid after suspension of
1
the crude product in Et2O and filtration: mp 236−243 °C; H NMR
(400 MHz, DMSO-d6) δ ppm 9.57 (1 H, br s), 8.97 (1 H, br s), 8.51
(1 H, br s), 8.31 (1 H, br s), 7.72 (1 H, br s), 7.67 (1 H, br s), 7.55 (1
H, br s), 7.38−7.51 (2 H, m), 6.89−7.08 (1 H, m), 2.24 (3 H, br s),
1.48 (9 H, br s); 13C NMR (101 MHz, DMSO-d6) δ ppm 170.9, 161.1,
156.9, 153.6, 152.7, 140.3, 136.4, 135.3, 132.2, 129.0, 127.0, 126.0,
125.9, 125.6, 122.5, 118.2, 118.0, 109.7, 79.3, 67.0, 28.1, 25.1, 13.5;
HRMS (ESI) calcd for C23H22N4O3S2 [M + 1]+ m/z 467.1212, found
467.1207; IR (film, cm−1) 3273, 2978, 2928, 2362, 2337, 1695, 1653,
1576, 1537, 1438, 1290, 1243, 1158.
tert-Butyl (3-(6-Benzyl-2-(methylthio)-7-oxopyrido[2,3-d]-
pyrimidin-8(7H)-yl)phenyl)carbamate (8f). The title compound was
prepared according to the standard procedure. The crude material was
chromatographed (using a gradient of 0−10% EtOAc in DCM). This
material was contaminated with unreacted starting material. The solid
was suspended in Et2O with sonication, filtered using a medium
porosity sintered glass frit, and washed with Et2O, affording the title
1-(2,4-Difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one
(12a). The title compound was prepared according to the standard
procedure, except 3 equiv of LiHMDS was used and the reaction was
allowed to run for 2 days. The crude material was chromatographed
(using a gradient of 0−80% EtOAc in hexanes), affording the title
1
compound (825 mg, 31%) as a fine white solid: mp 244−251 °C; H
NMR (400 MHz, MeOH/CDCl3 mixture) δ ppm 8.52 (1 H, s), 7.48
(1 H, br s), 7.30−7.42 (6 H, m), 7.22−7.30 (3 H, m), 6.82−6.90 (1 H,
m), 3.91 (2 H, s), 2.14 (3 H, s), 1.41−1.54 (9 H, s); 13C NMR (101
MHz, MeOH/CDCl3 mixture) δ ppm 172.2, 163.3, 155.6, 154.2,
153.3, 140.2, 137.8, 136.1, 134.8, 132.8, 129.4, 129.3, 128.7, 126.7,
122.4, 118.5, 109.3, 36.5, 28.1, 13.7; HRMS (ESI) calcd for
C26H26N4O3S [M + 1]+ m/z 475.1805, found 475.1801; IR (film,
cm−1) 3292, 2980, 2922, 2361, 2338, 1704, 1652, 1575, 1549, 1531,
1436, 1368, 1287, 1244, 1167, 1154.
1
compound (160 mg, 58%) as a yellow solid: mp 203−214 °C; H
NMR (400 MHz, DMSO-d6) δ ppm 11.58 (1 H, br s), 8.19 (1 H, br
s), 8.10 (1 H, d, J = 7.6 Hz), 7.66−7.84 (1 H, m), 7.57 (1 H, br s),
7.31 (1 H, br s), 6.57 (1 H, d, J = 7.6 Hz); 13C NMR (101 MHz,
DMSO-d6) δ ppm 164.1, 161.9 (dd, J = 0.001, 0.02, Hz), 156.9 (dd, J
= 0.001, 0.02, Hz), 149.5, 134.5 (d, J = 0.019, Hz), 130.5 (d, J = 0.001,
Hz), 112.1 (dd, J = 0.0004, 0.002, Hz), 108.5 (d, J = 0.015, Hz), 105.2
(dd, J = 0.002, 0.003, Hz); HRMS (ESI) calcd for C12H7F2N3O [M +
1]+ m/z 248.0636, found 248.0635; IR (film, cm−1) 3063, 2786, 2361,
2338, 1653, 1528, 1264, 1193, 1107.
8-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10a).
The title compound was prepared according to the standard
procedure. The crude material was chromatographed (using a gradient
of 20−100% EtOAc in hexanes), affording the title compound (950
1-Cyclopropyl-7-(4-methoxybenzyl)pyrido[2,3-d]pyridazine-2,8-
(1H,7H)-dione (12b). The title compound was prepared according to
the standard procedure, except 2.5 equiv of LiHMDS was used and the
reaction was allowed to run for 5 h. The crude material was
chromatographed (using a gradient of 0−30% EtOAc in hexanes),
affording the title compound (127 mg, 52%) as a light yellow
crystalline solid: mp 140−158 °C; 1H NMR (400 MHz, chloroform-d)
δ ppm 7.81 (1 H, s), 7.42 (3 H, d, J = 5.3 Hz), 6.85 (2 H, d, J = 7.0
Hz), 6.80 (1 H, d, J = 9.4 Hz), 5.24−5.34 (2 H, m), 3.78 (3 H, s),
3.50−3.61 (1 H, m), 1.19−1.36 (2 H, m), 0.62 (2 H, br s); 13C NMR
(101 MHz, chloroform-d) δ ppm 163.5, 159.4, 153.7, 137.6, 135.2,
1
mg, 85%) as a yellow crystalline solid: mp 177−192 °C; H NMR
(400 MHz, DMSO-d6) δ ppm 8.88 (1 H, s), 7.94 (1 H, d, J = 9.6 Hz),
6.64 (1 H, d, J = 9.6 Hz), 3.60 (3 H, s), 2.61 (3 H, s); 13C NMR (101
MHz, DMSO-d6) δ ppm 171.8, 162.2, 157.0, 154.2, 136.1, 121.1,
109.5, 27.4, 13.9; HRMS (ESI) calcd for C9H9N3OS [M + 1]+ m/z
208.0545, found 208.0548; IR (film, cm−1) 2930, 2362, 2337, 1672,
1611, 1571, 1530, 1368, 1283, 1170, 1131.
5,8-Dimethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one
(10b). The title compound was prepared according to the standard
3264
dx.doi.org/10.1021/jo500284n | J. Org. Chem. 2014, 79, 3260−3266

The Journal of Organic Chemistry
Note
134.3, 130.2, 128.5, 127.6, 117.3, 114.0, 55.3, 31.4, 10.9; HRMS (ESI)
calcd for C18H17N3O3 [M + 1]+ m/z 324.1349, found 324.1344; IR
(film, cm−1) 2955, 2836, 2362, 2338, 1673, 1652, 1610, 1512, 1247.
2-Chloro-8-ethyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
(12c). The title compound was prepared according to the standard
procedure. The crude material was chromatographed (using a gradient
of 20−80% EtOAc in hexanes), affording the title compound (444 mg,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rwurz@amgen.com.
Notes
■
1
58%) as a white crystalline solid: mp 180−181 °C; H NMR (400
MHz, chloroform-d) δ ppm 8.76 (1 H, s), 6.58 (1 H, s), 4.44 (2 H, q, J
= 7.0 Hz), 2.47 (3 H, s), 1.54 (2 H, s), 1.32 (3 H, t, J = 6.9 Hz); 13C
NMR (101 MHz, DMSO-d6) δ ppm 161.1, 159.2, 157.4, 155.2, 145.1,
122.1, 113.0, 35.7, 16.9, 12.8; HRMS (ESI) calcd for C10H10ClN3O
[M + 1]+ m/z 224.0591, found 224.0588; IR (film, cm−1) 3338, 2980,
2935, 2361, 2338, 1665, 1580, 1460, 1378, 1330, 1265, 1198.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-Chloro-8-isopropyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
(12d). The title compound was prepared according to the standard
procedure. The crude material was chromatographed (using a gradient
of 20−80% EtOAc in hexanes), affording the title compound (265 mg,
T.A. is grateful to Philip Tagari for supporting the summer
internship program at Amgen. The authors would also like to
thank Dr. Liping Pettus and Dr. Andrew Tasker for helpful
discussions.
1
71%) as a light yellow solid: mp 142−144 °C; H NMR (400 MHz,
chloroform-d) δ ppm 8.74 (1 H, s), 6.53 (1 H, d, J = 1.2 Hz), 5.74 (1
H, dt, J = 13.8, 6.9 Hz), 2.44 (3 H, d, J = 1.4 Hz), 1.61 (6 H, d, J = 6.8
Hz); 13C NMR (101 MHz, DMSO-d6) δ ppm 161.8, 158.4, 157.4,
155.6, 144.7, 122.9, 113.3, 45.5, 19.1, 16.7; HRMS (ESI) calcd for
C11H12ClN3O [M + 1]+ m/z 238.0748, found 238.0749; IR (film,
cm−1) 3429, 3332, 3214, 3068, 2985, 2940, 2362, 2338, 1667, 1594,
1568, 1524, 1509, 1434, 1302.
2-Chloro-8-(2,4-dimethoxybenzyl)-5-methylpyrido[2,3-d]-
pyrimidin-7(8H)-one (12e). The title compound was prepared
according to the standard procedure. The crude material was
chromatographed (using a gradient of 0−80% EtOAc in hexanes),
affording the title compound (148 mg, 62%) as a pale yellow
crystalline solid: mp 164−187 °C; 1H NMR (400 MHz, DMSO-d6) δ
ppm 9.10 (1 H, s), 6.71 (1 H, s), 6.60 (1 H, s), 6.50 (1 H, d, J = 8.2
Hz), 6.34 (1 H, d, J = 8.2 Hz), 5.30 (2 H, s), 3.85 (3 H, s), 3.72 (3 H,
s), 2.52 (3 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 161.3,
159.6, 159.1, 157.5, 155.7, 145.6, 126.4, 122.1, 115.9, 113.0, 104.5,
98.4, 55.6, 55.2, 17.0; HRMS (ESI) calcd for C17H16ClN3O3 [M + 1]+
m/z 346.0959, found 346.0959; IR (film, cm−1) 2957, 2837, 2361,
2336, 1671, 1616, 1568, 1534, 1508, 1460, 1358.
tert-Butyl (3-(6-Methoxy-5-methyl-2-(methylthio)-7-oxopyrido-
[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (13). The title com-
pound was prepared according to the standard procedure, except at 2
h reaction time, Martin sulfurane (1.0 equiv) was added to the reaction
mixture and it was allowed to stir at room temperature for 3 h. The
crude material was chromatographed (using a gradient of 0−60%
EtOAc in hexanes), affording the title compound (142 mg, 50%) as an
off-white crystalline solid: mp 188−194 °C; 1H NMR (400 MHz,
DMSO-d6) δ ppm 9.55 (1 H, br s), 8.98 (1 H, s), 7.34−7.53 (3 H, m),
6.91 (1 H, d, J = 7.4 Hz), 3.83 (3 H, s), 2.43 (3 H, s), 2.20 (3 H, s),
1.47 (9 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 169.6, 158.7,
154.7, 152.7, 152.2, 144.9, 140.2, 136.0, 131.3, 129.0, 122.5, 118.2,
118.0, 110.0, 79.3, 59.6, 28.1, 13.4, 10.2; HRMS (ESI) calcd for
C21H24N4O4S [M + 1]+ m/z 429.1597, found 429.1591; IR (film,
cm−1) 3304, 2977, 2929, 1724, 1662, 1607, 1571, 1527, 1429, 1161.
tert-Butyl (3-(6-Deuterio-2-(methylthio)-7-oxopyrido[2,3-d]-
pyrimidin-8(7H)-yl)phenyl)carbamate (14). The title compound
was prepared according to the standard procedure using deuterio
EtOAc in place of EtOAc. The crude material was chromatographed
(using a gradient of 0−80% EtOAc in hexanes), affording the title
compound (198 mg, 74%) as a pale yellow crystalline solid: mp 217−
226 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (1 H, br s), 8.94
(1 H, s), 8.04 (1 H, s), 7.33−7.57 (3 H, m), 6.85−6.97 (1 H, m), 2.21
(3 H, s), 1.47 (9 H, s); 13C NMR (101 MHz, DMSO-d6) δ ppm 171.5,
162.0, 157.0, 154.9, 152.7, 140.3, 136.9, 135.9, 129.0, 122.4, 118.1,
117.9, 109.5, 79.3, 40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 38.9, 28.1, 13.5;
HRMS (ESI) calcd for C19H19DN4O3S [M + 1]+ m/z 386.1398, found
386.1395; IR (film, cm−1) 3291, 2977, 2928, 2362, 2338, 1721, 1662,
1605, 1571, 1430, 1362, 1161.
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3265
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The Journal of Organic Chemistry
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Strick, C. A.; Williams, V. A.; Zhang, L. J. Med. Chem. 2009, 52, 3576−
3585. This report does not contain any examples involving
substitution on N-1 of the pyridinone.
(16) For a discussion on the preparation of a lithium enolate of ethyl
acetate using LiHMDS, see: Rathke, M. W. J. Am. Chem. Soc. 1970, 92,
3222−3223.
(17) LC-MS analysis of the reaction mixtures at earlier time points
(e.g., 30 min) shows a mass consistent with protonated form of
intermediate 6. This intermediate gradually disappears as the reaction
progress, and the intensity of the desired product 7a increases.
(18) Generation of an enolate from catalytic amounts of TBAF and
trimethylsilyl ethylacetate in situ also gave the desired product 7a but
with lower yields (ca. 50%). For leading references using this
approach, see: (a) Nakamura, E.; Shimizu, M.; Kuwajima, I.
Tetrahedron Lett. 1976, 17, 1699−1702. (b) Wadhwa, K.; Verkade, J.
G. J. Org. Chem. 2009, 74, 4368−4371.
(19) This reaction was successfully run on an 80 g scale to furnish 7c
in comparable yields following extraction of the reaction mixture with
EtOAc, suspension of the product in Et2O, and filtration.
(20) The mass balance was unreacted starting material from this
reaction.
(21) The conditions outlined in ref 4 (K2CO3, DMF, 110 °C, 3 h)
did not furnish product due to the decreased reactivities of N-
bis(arylated) aminoaldehydes.
(22) Use of ethyl 4-nitrophenylacetate was also attempted at a
reviewer’s request and found not to be a competent substrate for the
cyclization (unreacted starting material was recovered).
(23) Other dehydrating agents also are effective as well as including
commercially available Burgess reagent (1 equiv, 40% yield after 8 h).
(24) This methodology has been used successfully to install a 13C
radiolabel into compound 7a (data not shown).
(25) When the reaction was run on a 0.5 g scale using 3 equiv of
EtOAc-d8 and otherwise identical conditions, a 93:7 ratio of deuterio/
nondeuterio 14 was observed (isolated yield = 72%).
(26) Chang, S.; Zhang, L.; Xu, S.; Luo, J.; Lu, X.; Zhang, Z.; Xu, T.;
Liu, Y.; Tu, Z.; Xu, Y.; Ren, X.; Geng, M.; Ding, J.; Pei, D.; Ding, K. J.
Med. Chem. 2012, 55, 2711−2723.
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