2-(Substituted amino)-8-Azachromones from 4,6-Diaryl-2-pyridones: A Synthetic Strategy toward Compounds of Broad Structural Diversity

Article abstract of DOI:10.1021/acs.joc.0c01561

3-Acetoacetyl-4,6-diaryl-2-pyridones are synthesized in three steps from chalcones and then condense with carbon disulfide to afford 8-Azachromones containing a methylthio group at C2. This leaving group offers an entry point for the insertion of more com

Full text of DOI:10.1021/acs.joc.0c01561

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Article
2-(Substituted amino)-8-azachromones from 4,6-Diaryl-2-pyridones: a
Synthetic Strategy toward Compounds of Broad Structural Diversity
Steve Saulnier, Rayane Ghoteimi, Christophe Mathé, Suzanne Peyrottes, and Jean-Pierre Uttaro
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01561 • Publication Date (Web): 01 Sep 2020
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The Journal of Organic Chemistry
2-(Substituted amino)-8-azachromones from 4,6-Diaryl-2-pyridones: a Synthetic
Strategy toward Compounds of Broad Structural Diversity
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Steve Saulnier, Rayane Ghoteimi, Christophe Mathé, Suzanne Peyrottes and Jean-Pierre Uttaro*
Nucleosides & Phosphorylated Effectors Team, Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de
Montpellier, Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier, France.
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ABSTRACT
3-Acetoacetyl-4,6-diaryl-2-pyridones are synthesized in three steps from chalcones and then
condense with carbon disulfide to afford 8-azachromones containing a methylthio group at C2. This leaving
group offers an entry point for the insertion of more complex moieties via nucleophilic substitution. For this
purpose, N-nucleophiles are explored according to their positions in the Mayr’s nucleophilicity scale (N
parameter), and three main classes are distinguished depending on whether the substitution takes place from
their neutral forms, from their deprotonated anionic forms, or under nucleophilic catalysis. A broad range of
primary and secondary amines may be inserted by this method, including enantiomerically pure amino acids,
enabling us to explore structural diversity.
TABLE OF CONTENTS GRAPHIC
R1
R1
R1
N parameter
O
O
O
O
O
O
1. DBU, CS2
2. Me2SO4
O
O
O
HNR2R3
R2
Ph
N
N
R3
Ph
N
H
Ph
N
SMe
87-91%
30 examples
R1 = H, Cl, Br, Ot-Bu or morpholino
R2 and R3 = H, alkyl and/or aryl
36-98% yields
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INTRODUCTION
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The 8-azachromone core was synthesized for the first time in 1967 from 1,3-diketone derivatives of
2-pyridones by an acid-catalyzed ring closure.1 Since then, few methods have been developed in comparison
with the isostere chromones,2 although both scaffolds might have similar biological and pharmaceutical
properties.3 The electron-deficient nature of the pyridine ring is often pointed out as an issue to the
challenging access to 8-azachromones. To date, most of the reported procedures still involve 1,3-diketones
and fall into two approaches according to whether the ring closure takes place via intramolecular O-arylation
or via condensation with carbon disulfide (Scheme 1). The intramolecular O-arylation has been the most
explored and can be performed under acid catalysis for 2-pyridones1,4 and 2-methoxypyridines,5 under base
catalysis for 2-halopyridines,6 and via CH activation of N-oxides for 2-unsubstituted pyridine derivatives7
(Scheme 1A). By contrast, the condensation with CS2 was reported solely in the case of 4,6-dimethyl-2-
pyridone derivatives (Scheme 1B)8 and has not received further attention. Yet, the methylthio leaving group
at the electrophilic site C2 on the cyclization product II would enable to access more complex derivatives
III by simple nucleophilic substitution. Such derivatization would be more difficult from the O-arylation
products I.
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Scheme 1. Synthesis of 8-Azachromones from 1,3-Diketone Precursors.
A. Intramolecular O-arylations (ref. 1, 4-7)
H+, heat (X = OH, OMe)
or K2CO3, heat (X = Cl, Br)
O
X
O
O
O
Y
R
R
or
N
N
Y
m-CPBA, activation conditions
(X = H)
Y = alkyl, aryl
I
B. Condensation with carbon disulfide and nucleophilic substitution
(R = methyl, ref. 8 ; R = aryl, this work)
R
O
O
O
R
N
O
O
R
N
O
O
O
Base, CS2, Me2SO4
NuH
R
N
H
R
O
SMe
R
Nu
II
III
The present work revisits the condensation with CS2 and further explores possibilities of nucleophilic
substitution at C2 (Scheme 1B). We focus on 5,7-diaryl-8-azachromone derivatives because aryl substituents
on the pyridine ring have not yet been considered by the synthetic methods mentioned above. We show that
primary and secondary amines are well suited for the nucleophilic substitution and that they give rise to 2-
(substituted amino)-8-azachromones under conditions that mainly depend on the nucleophile strength and
position in the Mayr’s nucleophilicity scale.9 The synthesis of the 1,3-diketone cyclization precursors,
namely 3-acetoacetyl-4,6-diaryl-2-pyridones, is also described, as they are not easily accessible.
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The Journal of Organic Chemistry
RESULTS AND DISCUSSION
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Synthesis of 3-Acetoacetyl-4,6-diaryl-2-pyridones. The 1,3-diketones cyclization precursors are
commonly prepared by addition of a methyl Grignard reagent to the nitrile of 3-cyano-2-pyridones, followed
by Claisen condensation of the resulting 3-acetyl-2-pyridones. This approach has been well described in the
case of 4,5-dialkyl-2-pyridones but turned out to be more difficult with 4,5-diaryl derivatives.
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Among the numerous methods for the synthesis of the starting material, 4,5-diaryl-3-cyano-2-
pyridones 1, we focused on the base-promoted condensation between chalcones and cyanoacetamide (Table
1). An effective reported procedure involves potassium t-butoxide in DMSO under oxygen atmosphere.10
When conducted in open air, this procedure leads to a substantial amount of 3-unsubstituted 2-pyridones as
by-products of decyanative aromatization, instead of the desired 3-cyano-2-pyridones.11 This point is
responsible for the modest yield of product 1a (40%) obtained in open air (Table 1, entry 1), whereas an
88% yield was reported when using an oxygen atmosphere (data from ref. 10). As other procedures using
ethanol as solvent with different bases, and without the need for oxygen atmosphere were reported,12 we
evaluated the effect of replacing DMSO with ethanol, 2-propanol, and t-butyl alcohol, together with the
corresponding potassium alkoxide bases in open air (entries 2-5). Under these conditions, we did not
observe the decyanative aromatization by-product. The reaction rate clearly depends on the base strength:
although the reaction in ethanol/KOEt was still incomplete after 72 hours at room temperature (entries 2 and
3), a 96% yield of 1a was obtained after 60 hours in 2-propanol/KOi-Pr (entry 4) and 92% after only 24
hours using the more basic t-butyl alcohol/KOt-Bu medium (entry 5). The desired product 1a is initially
formed as potassium salt, and is soluble neither in 2-propanol nor in t-butyl alcohol under this form. We
took advantage of this insolubility to isolate and characterize 1a as potassium salt 1a-K in a simplified
reaction work-up. According to the same procedure, we prepared 3-cyano-2-pyridones 1b-e-K diversely
substituted in the para position of the 4-phenyl ring (Table 1, entries 6-9).
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Table 1. Synthesis of 3-Cyano-2-pyridones from 4-Substituted Chalcones and Cyanoacetamide.
1
2
3
R1
4
5
O
O
base
+
Ph
6
7
8
9
NC
solvent, air
NH2
CN
O
R1
Ph
N
H
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1a-e
Entrya
R1
Solvent
DMSO
Base
Temperature Reaction time, h Productb Yield, %c
1
2
3
4
5
6
7
8
9
H
KOt-Bu
KOEt
rt
2
1a
40
37
88
96
92
93
96
77
93
H
ethanol
rt
rt
20
72
60
24
60
60
60
48
1a-K
1a-K
1a-K
1a-K
1b-K
1c-K
1d-K
1e-K
H
ethanol
KOEt
H
2-propanol
KOi-Pr
KOt-Bu
KOi-Pr
KOi-Pr
KOi-Pr
KOt-Bu
rt
H
Cl
t-butyl alcohol
2-propanol
30 °C
rt
Br
2-propanol
rt
Ot-Bu
Morpholino
2-propanol
rt
t-butyl alcohol
30 °C
a Reaction conditions: 0.083 M chalcone, 1.1 equiv cyanoacetamide, 4 equiv base, open air. 1a-e-K refers to the
b
potassium salts of products 1a-e. c Yields of isolated products.
We assigned the position of the substituted phenyl ring on the basis of the probable reaction
mechanism: the Michael addition of cyanoacetamide to the 4-substituted chalcone leads to a condensation
product where the substituted phenyl ring would be adjacent to the 3-cyano group, i.e. at C4. This was later
confirmed on the 3-acetyl derivative 2c by the NOESY correlation between the acetyl group and the ortho
protons of the bromo-substituted phenyl ring (Figure 1).
Br
O
N
O
H
2c
Figure 1. Selected NOESY Correlations (Arrows) Showing the Position of the Substituted Phenyl
Ring.
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The Journal of Organic Chemistry
3-Acetyl-2-pyridones 2 might be obtained directly from chalcones by using acetoacetamide instead
of cyanoacetamide in the procedure described above. However, the reaction requires heating under reflux
and mainly gives the 3-unsubstituted products resulting from deacetylative aromatization. Therefore, the
addition of a methyl Grignard reagent to 3-cyano-2-pyridones appears to be the most reliable strategy to
access acetyl derivatives.
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Alkyl-substituted cyanopyridones are known to give addition products with methylmagnesium
bromide at room temperature.13 For aryl-substituted derivatives 1a-e-K, the use of a large excess of
MeMgBr and heating (65 °C) were required to reach a significant conversion. However, under these
conditions, halogenated derivatives 1b (R1 = Cl) and 1c (R1 = Br) gave rise to unidentified by-products due
to a possible halogen-magnesium exchange. We obtained better results with the more reactive
dimethylmagnesium generated in situ by the dioxane precipitation method: addition of 1,4-dioxane to
MeMgBr precipitates MgBr2 species as polymeric dioxane adducts and shifts the Schlenk equilibrium
toward Me2Mg.14 Thus, 3-cyano-2-pyridones 1a-e-K were converted to the corresponding 3-acetyl-2-
pyridones 2a-e at room temperature with 56-75% yields after hydrolysis of the imine intermediate products
(Scheme 2). The hydrolysis does not need strong acidic conditions and can be performed at pH around 7-8,
enabling to work with the acid-sensitive t-butyl ether derivative 2d.
Scheme 2. Two-Step Synthesis of 1,3-Diketones 3 from 3-Cyano-2-pyridones 1-K.
R1
R1
R1
1. NaH, dioxane, 1 h
2. EtOAc, 12 h
1. Me2Mg, THF, 48 h
O
O
O
O
O
CN
O
2. HCl, H2O, 40 °C, 12 h
3. NH4Cl, H2O
Ph
N-
Ph
N
H
Ph
N
H
K+
1-K
2
3
2a, 75%
2b, 68%
2c, 65%
2d, 56%
2e, 61%
3a, 84%
3b, 79%
3c, 72%
3d, 83%
3e, 75%
1a-K, 2a, 3a : R1 = H
1b-K, 2b, 3b : R1 = Cl
1c-K, 2c, 3c : R1 = Br
1d-K, 2d, 3d : R1 = Ot-Bu
1e-K, 2e, 3e : R1 = Morpholino
Finally, the Claisen condensation between 2a-e and ethyl acetate in dioxane led to the 1,3-diketone
derivatives 3a-e with yields of 72-84% (Scheme 2). These compounds were then considered as starting
materials for their cyclization into 8-azachromones.
Cyclization into 2-(Methylthio)-8-azachromones. The reported procedure uses potassium
hydroxide (two equivalents) as base to promote the condensation with CS2 (three equivalents) in DMSO,
followed by treatment with dimethyl sulfate (four equivalents).8,15 Under these conditions, diketone 3a gave
rise to a mixture of the 2-(methylthio)-8-azachromone 4a (34%) and of the 2-methyl derivative 5a (35%) as
intramolecular O-arylation by-product (Scheme 3). As discussed in the introduction, the O-arylation ring
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closure of 2-pyridones has been mainly reported through dehydration under acidic conditions, and 5a is
indeed the main product observed (89%) after a one hour treatment of 3a in sulfuric acid (Scheme 3).
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2
3
4
5
6
Scheme 3. Cyclization of Diketone 3a into 8-Azachromones According to Reported Procedures.
7
8
9
1. KOH, CS2, DMSO, 4 h
2. Me2SO4, 2 h
Ph
O
O
+
5a, 35%
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[Ref. 15]
Ph
O
O
O
Ph
N
O
SMe
4a, 34%
Ph
N
H
Ph
O
H2SO4, 1 h
[Ref. 4]
3a
Ph
N
O
5a, 89%
With the aim of maximizing the formation of 4a, the reaction conditions, including solvent nature,
base strength, equivalents of the reagents, and reaction time were screened and revealed the following
points. Firstly, the reaction requires polar solvents such as DMF, DMSO or acetonitrile. As solvent
nucleophilicity may be problematic, anhydrous acetonitrile appears to be the solvent of choice, furthermore
leading to the selective precipitation of product 4a in the reaction mixture. Secondly, the use of two
equivalents of a base at least as strong as K3PO4 is required. In this respect, DBU increases the solubility of
the deprotonated anionic species in acetonitrile, resulting in higher reaction rates. The third point concerns
the amount of CS2. Although one equivalent would theoretically be enough for the reaction to proceed, we
observed a decrease in the formation of the O-arylation by-product 5a when using higher amounts of CS2
(up to nine equivalents), thus resulting in a significant increase in the yield of 4a. On the basis of these
observations, we developed an improved procedure affording the 2-(methylthio)-8-azachromone derivatives
4a-e with average yields of 87-91% (Scheme 4).
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The Journal of Organic Chemistry
Scheme 4. Improved Conditions for the Cyclization of Diketones 3 into 2-(Methylthio)-8-
azachromones 4.
1
2
3
4
(Conditions: 0.1 M 3, 2.2 equiv DBU, 9 equiv CS2, 2.2 equiv Me2SO4, rt)
5
6
R1
R1
7
8
9
1. DBU, MeCN, 0.5 h
2. CS2, 4 h
O
O
O
O
O
O
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11
12
13
14
15
16
17
18
19
20
21
22
23
3. Me2SO4, 12 h
Ph
N
Ph
N
SMe
H
3
4
3a, 4a : R1 = H
4a, 91%
4b, 87%
4c, 88%
4d, 89%
4e, 89%
3b, 4b : R1 = Cl
3c, 4c : R1 = Br
3d, 4d : R1 = Ot-Bu
3e, 4e : R1 = Morpholino
To explain the formation of both cyclization products 4 and 5, we propose a mechanism in Scheme 5.
This mechanism works on the assumption that dianionic species would not be formed under the conditions
of Scheme 3 (KOH, DMSO) or Scheme 4 (DBU, acetonitrile). Deprotonation of diketone 3 gives rise to the
multident nucleophilic species A and B in equilibrium. They may react with CS2 through the oxygen atom of
the pyridone ring or through the enolate, leading to species C and D, respectively (among other possible
reactive sites and intermediate species). The reaction via the enolate carbon atom may be considered as
thermodynamically favored, so that the whole equilibrium is shifted toward D, which would then lead to
product 4 through two possible paths depending on whether the ring closure takes place via a 6-exo-trig
(path A) or a 6-endo-trig reaction (path B). In path B, the thioenolate of H is first alkylated by either
Me2SO4 or CS2, the latter explaining the need for an excess of CS2. Product 5, however, would be formed
from species C after methylation of the dithiocarbonate group, giving K and the corresponding anionic
species L. The leaving group S-methyl dithiocarbonate at C2 enables the intramolecular O-arylation that
leads to 5. Actually, this mechanism might involve more complex intermediate species as the above
assumption about the absence of dianionic species may not be valid.
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Scheme 5. Plausible Reaction Mechanism for the Formation of Products 4 and 5.
1
2
(Counter ions and reversibility of reaction steps are not shown)
3
4
5
6
7
8
9
Ar O-
O
Ar
O
O
O
Ar
N-
O
O
O
base
base
+/- H+
+/- H+
Ph
N
H
Ph
N
H
O
Ph
A
3
B
base = DBU or KOH
Z = Me or CS2Me
10
11
12
13
14
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CS2
O
CS2
O
Ar
N
O
O
Ar
Ph
O
S-
S
O
Ph
N
H
S
S-
D
C
Path A
O
O
Ar
N
O
O
O
Ar
N
O
O
O
Ar
Me2SO4
Me2SO4
- MeSH
base
D
4
SMe
SMe
SMe
SMe
Ph
Ph
S
O
Ph
N
S-
H
F
G
E
Path B
base
O
O
O
Ar
O
CS2 then Me2SO4
(Z = CS2Me)
Ar
- ZSH
4
or
SMe
SMe
-S
O
S
Z
Ph
O-
N
H
O
Ph
N
H
Me2SO4 (Z = Me)
H
J
Ar
N
O
O
Ar
N
O
O
Ar
O
O
- MeSCOS-
Me2SO4
base
C
Ph
O
Ph
Ph
N
S
SMe
S
SMe
5
K
L
Nucleophilic Substitution of the Methylthio Group. Our approach to exploring the scope of the
nucleophilic substitution is based on the Mayr’s reactivity scales. These scales are constructed according to
the equation log k = s (N + E), where the second-order rate constant k of a nucleophile-electrophile
combination correlates with the nucleophilicity and electrophilicity parameters N and E of the reagents.9
Values of N and E parameters of many reagents have been determined,16 so that these scales allow
predicting the feasibility of a wide variety of combinations. A given electrophile such as 4a that reacts with
a nucleophile referenced in the nucleophilicity scale (i.e. with a known N parameter), will be expected to
react with other nucleophiles of similar or higher N parameters as well. Among the different π-, n- and σ-
nucleophiles characterized in the Mayr’s scales, we focused on neutral NH-type nucleophiles because they
cover a wide range of nucleophilicity: basically, from N 7.69 for benzotriazole to N 18.52 for pyrrolidine
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The Journal of Organic Chemistry
(data in acetonitrile, which was chosen as reference solvent for this work). This means roughly eleven units.
In comparison, alcohols cover only six units and are significantly less nucleophilic.
1
2
3
4
5
6
7
8
9
Therefore, we explored the reactivity of 4a with some N-nucleophiles, starting from piperidine (N
17.35) and decreasing in nucleophilicity (Table 2). We observed the nucleophilic substitution in methylene
chloride at room temperature until ethanolamine (N 14.11, entry 5) and glycine methyl ester (N 13.51 for
potassium glycinate, data in water, entry 6). Under the same conditions, p-anisidine (N 13.42) only led to
traces of the substitution product 6ag, and weaker nucleophiles such as aniline (N 12.64) and benzocaine did
not react at all, even upon heating at 65 °C in THF. Thus, a first limit in reactivity is reached for N value of
approximately 13.5. Nucleophiles located above this limit give substitution products with 4a whereas
nucleophiles below do not, at least without further activation conditions.
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To extend the scope of reactivity, we envisaged activation via nucleophilic catalysis. Because they
show N parameter values above the limit of 13.5, DBU (N 15.29), DMAP (N 15.51) and DABCO (N 18.80)
were expected to react with 4a and to give rise to the corresponding positively charged intermediates of
enhanced electrophile strengths. Indeed, all three catalysts enabled the nucleophilic substitution with p-
anisidine and aniline, DMAP being the most effective with 90-91% yields of 6ag and 6ah after only two
hours at 65 °C in THF (Table 2, entries 7 and 8). However, the efficacy of nucleophilic catalysis is quite
limited as benzocaine required 36 hours at 100 °C in dioxane to afford 61% of the substitution product 6ai
(entry 9), and 2-methylimidazole (N 11.74) and imidazole (N 11.47) were completely unreactive under the
same conditions (entries 10 and 11). Therefore, a second limit is reached for N value of about 12, above
which the presence of DMAP enables the nucleophilic substitution.
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Table 2. Nucleophilic Substitution of 4a with N-Nucleophiles Depending on the Nucleophilicity
1
2
3
Parameter N.
4
5
6
7
8
9
Ph
N
O
O
O
Ph
N
O
O
O
HNR2R3
R2
solvent, conditions
Ph
N
R3
Ph
SMe
4a
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entrya
HNR2R3
N
Catalyst Solvent Temperature Time, Product Yield,
c
parameterb
h
%
HN
1
2
17.35
none
none
DCM
DCM
rt
rt
12
6aa
6ab
96
HN
O
15.65
12
93
MeNH2
3
4
15.19
14.29
none
none
DCM
DCM
rt
rt
12
12
6ac
6ad
97
94
H2N
Ph
OH
5
14.11
none
none
DCM
DCM
rt
rt
12
12
6ae
6af
65
63
H2N
6d
13.51e
H2N
CO2Me
7f
8f
9f
13.42
12.64
n/ag
DMAP
DMAP
THF
THF
65 °C
65 °C
2
2
6ag
6ah
6ai
91
90
61
H2N
OMe
H2N
H2N
CO2Et
DMAP dioxane
DMAP dioxane
100 °C
36
N
10f
11f
11.74
11.47
100 °C
100 °C
12
12
0
0
N
H
N
DMAP dioxane
N
H
a Reaction conditions: 0.1 M 4a and 1.1 equiv Nu. b N parameters are given in acetonitrile, data from ref. 16. c Yields
of isolated products. d Glycine methyl ester was generated from the corresponding hydrochloride (1.5 equiv) and Et3N
(1.1 equiv). e N parameter of the free carboxylate, data in water. f 0.05 M 4a. g Data not yet available.
It is important to note that the products presented in Table 2 were obtained with one equivalent of
nucleophile. With an excess, a second substitution takes place and leads to the 2-pyridone derivatives 7 by
ring opening, due to the leaving group ability of the pyridone moiety. This second substitution works best
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The Journal of Organic Chemistry
with cyclic secondary amines and becomes more difficult when the nucleophile strength decreases. In the
presence of three equivalents of piperidine, 4a was completely converted into the open-ring product 7a after
36 hours, whereas with morpholine only 72% of 7b were obtained after 60 hours (Scheme 6). The ring
opening of the 8-azachromone scaffold in the presence of N-nucleophiles was reported in 2003 for 2-
polyfluoroalkyl derivatives.17 Curiously, in that case the reaction worked well with primary amines whereas
piperidine and morpholine did not give open-ring products but the addition products 2-morpholino- and 2-
piperidino- 8-azachromanones instead.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Formation of Open-Ring Products by Two Consecutive Nucleophilic Substitutions.
X
Ph
N
O
O
N
CH2Cl2
O
O
Ph
+ HN
X
N
rt, 36-60 h
X
Ph
O
SMe
3 equiv
O
N
H
Ph
4a
7
7a : X = CH2, 98%
7b : X = O, 72%
The N values of 13.5 and 12 mentioned above allow predicting the nucleophilic substitution with a
given nucleophile and were exemplified for the 5,7-diphenyl derivative 4a, playing the role of constant
electrophile strength. Nevertheless, these data may also be applied to the R1-substituted derivatives 4b-e as
were observed that the presence of a para substituent on the 5-phenyl ring does not significantly affect the
13
chemical properties of the azachromone core. This is revealed by comparing the C chemical shifts of the
azachromone scaffolds of compounds 4b-e with those of 4a (Table 3). Beside slight variations for carbon C5
(up to 1.3 ppm), the chemical shifts are almost identical, especially the chemical shifts of C2 and C4 (less
than 0.4 ppm variations) which are directly connected to the electrophilicity. Therefore, compounds 4a-e can
be considered of similar electrophile strengths and the limits in reactivity that were determined for 4a can be
used with compounds 4b-e as well.
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Table 3. Influence of the R1 Substituents on the 13C NMR Data of the 8-Azachromone Scaffold.
1
2
3
R1
4
5
6
7
8
O
O
5
10
9
3
2
6
7
4
9
Ph
N
O
SMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4a-e
13C NMR (CDCl3), δC, ppm
R1
C2
C3
C4
C5
C6
C7
C9
C10
H
Cl
177.4
177.6
177.6
177.1
177.1
119.9
119.8
119.8
119.9
119.9
174.6
174.6
174.5
174.7
175.0
155.3
154.0
154.0
155.1
155.1
122.6
122.4
122.3
122.7
122.5
159.0
159.3
159.3
158.9
158.8
160.8
160.8
160.8
160.9
161.1
114.2
114.1
114.0
114.2
114.0
Br
Ot-Bu
Morpholino
Scheme 7 shows examples of substitution products that were obtained from 4a-e according to the
reaction conditions developed. Briefly, aliphatic primary amines were inserted in methylene chloride at
room temperature (conditions A) whereas aromatic primary amines were inserted in dioxane at 85-100 °C in
the presence of DMAP (conditions B). Enantiomerically pure amino acid methyl esters (phenylalanine,
tyrosine, tryptophan and histidine) afforded substitution products according to conditions A with yields
ranging from 43% to 81%. Under the conditions of Scheme 7, no significant racemization was observed and
the products 6aj-am and 6bb can almost be considered as enantiomerically pure (see specific rotations in the
experimental section). This feature is interesting because most of amino acids and peptides have primary
amino groups of similar nucleophilicities18 and, therefore, may be inserted to the 8-azachromone scaffold in
this way without loss of optical activity.
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The Journal of Organic Chemistry
Scheme 7. Nucleophilic Substitution of 4a-e with Primary Aliphatic and Aromatic Amines.
1
2
3
R1
R1
4
5
6
7
8
9
H2NR2
O
O
O
O
O
O
Conditions A or B
Ph
N
SMe
Ph
N
NHR2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
6
4a-e
Ph
N
O
O
Ph
N
O
O
O
Ph
O
O
NH
OH
Ph
Cl
O
NH
Ph
NH
Ph
N
O
NH
Ph
MeO2C
MeO2C
6aj, 71%a,c
MeO2C
6ak, 75%a,c
6al, 81%a,c
Cl
Ph
N
O
O
O
O
O
O
O
O
Ph
NH
N
NH
OH
MeO2C
Ph
N
O
NH
Ph
N
N
H
Ph
6am, 43%a,d
MeO2C
6ba, 98%a
6bb, 74%a,c
Cl
N
Br
Br
Br
O
O
O
O
O
O
O
O
O
O
O
O
38
Ph
NH
Ph
N
NH
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
N
N
Ph
Ph
N
NHMe
H
6ca, 91%a
6cb, 89%a
CO2Et
CO2Et
6bc, 61%b
6cc, 67%b
Ot-Bu
O
O
N
Ot-Bu
N
N
O
O
O
O
O
O
O
Ph
N
O
NH
O
O
Ph
N
O
NHMe
Ph
N
H
Ph
6da, 95%a
Ph
N
O
NHPh
6eb, 89%b
CO2Et
6ea, 81%a
6db, 38%b
a Conditions A: 0.05-0.1 M 4, 1.1 equiv amine, DCM, rt. b Conditions B: 0.05 M 4, 1.1 equiv amine, 0.3 equiv DMAP,
c
1,4-dioxane, 85-100 °C. Amino acid methyl ester generated from the corresponding hydrochloride (1.5 equiv) and
Et3N (1.1 equiv). d Histidine methyl ester generated from the dihydrochloride (1.2 equiv) and Et3N (2 equiv).
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So far, only N-nucleophiles at least as nucleophilic as benzocaine enabled the formation of
substitution products. When the N value falls below the limit of N 12, the nucleophilic substitution does not
take place. Accordingly, imidazole with N 11.47 is unreactive. However, imidazole is relatively acidic with
a pKa of 18.6 in DMSO19 and, under anionic form, shows a significant increase in nucleophilicity to N 21.09
(data in DMSO),20 which is above the limit of reactivity. Thus, after deprotonation in the presence of KOt-
Bu in THF, the potassium salt of imidazole indeed reacts with 4a as predicted, but the product is quite
unstable and unfortunately could not be isolated. However, primary amines of similar nucleophile strengths
(i.e. unreactive under the conditions of Scheme 7), such as methyl and ethyl 5-aminopicolinate and 3-
aminoisoxazole, also react with 4a upon deprotonation by KOt-Bu in THF, but this time give stable products
that were isolated and clearly identified as substitution products 6an-ap (Scheme 8). The reaction is actually
complicated by two distinctive features that cap the yields at 50%: on the first hand, deprotonation of the
substitution product by the amine anion that would require two equivalents for a complete conversion, but
on the other hand the fast ring opening of the substitution product that prevents the use of a second
equivalent of amine anion. Nevertheless, this strategy enables the formation of substitution products that
would not be possible under neutral conditions, and was successfully applied to the R1-substituted
derivatives 4b-e (Scheme 8).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
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The Journal of Organic Chemistry
Scheme 8. Nucleophilic Substitution of 4a-e with Amine Anions.a
1
2
3
R1
R1
4
5
6
7
8
HNR2R3, KOt-Bu
O
O
O
O
O
O
THF, rt, 12 h
R2
9
Ph
N
N
R3
Ph
N
SMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4a-e
6
Ph
N
O
O
Ph
N
O
O
O
Ph
N
O
O
Ph
O
NH
Ph
NH
Ph
O
NH
N
O
N
N
CO2Me
CO2Et
6ap, 38%
6an, 41%
6ao, 47%
O
N
Cl
N
Br
Ot-Bu
O
O
O
O
O
O
O
O
O
O
O
Ph
NH
Ph
N
NH
Ph
N
O
NH
32
Ph
N
NH
33
34
35
36
37
38
39
40
N
N
N
N
CO2Et
CO2Et
CO2Me
CO2Me
6bd, 46%
6cd, 48%
6dc, 49%
6ec, 36%
a Reaction conditions: 0.05 M 4, 1.5 equiv amine, 1.1 equiv KOt-Bu, anhyd THF, rt, argon atm.
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The activation via deprotonation, which is possible with N-nucleophiles, might not be effective for
other classes of nucleophiles as the basicity of the reaction medium has to be taken into consideration. For
example, the O-nucleophiles water (N 5.20) and methanol (N 7.54) would need deprotonation to give
substitution products. However, the corresponding hydroxide and methoxide anions are much more basic
than the amine anions used in Scheme 8, and thus deprotonate the 2-(methylthio)-8-azachromone starting
materials, resulting in more difficult reactions. Nevertheless, neutral nucleophiles of any class with N values
above 12 in the Mayr’s nucleophilicity scale (e.g. enamines) should give the corresponding substitution
products in the same way than N-nucleophiles do.
CONCLUSION
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We have developed an efficient strategy enabling the synthesis of 2-(substituted amino)-8-
azachromones. This strategy relies on three main steps: the synthesis of 3-acetoacetyl derivatives of 4,6-
diaryl-2-pyridones, their cyclization into 2-(methylthio)-8-azachromones via condensation with carbon
disulfide, and finally the insertion of amines at C2 by nucleophilic substitution. Three main classes of
amines have been distinguished according to the conditions promoting the nucleophilic substitution, which
in turn depend on the nucleophile strength. The position of a given amine into one of those three classes is
easily predicted by using the Mayr’s nucleophilicity scale. Because the nucleophilic substitution is not
altered by the presence of a para substituent on the 5-phenyl ring, numerous structural analogs can be
designed. Our synthetic strategy paves the way for a greater access to new compounds of possible
pharmaceutical interest. This may be driven by the pharmaceutical properties of many N-substituted 2-
amino-chromones, including anti-platelet aggregation, kinase inhibition in anti-cancer therapies, anti-
inflammatory and antibacterial drugs.3a,21
1
2
3
4
5
6
7
8
9
10
11
12
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15
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17
18
19
20
21
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29
30
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32
33
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35
36
37
38
39
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60
EXPERIMENTAL SECTION
General remarks. Commercially available reagents and solvents were used as purchased without
1
13
further purification, unless otherwise indicated. H and C NMR spectra were recorded on 400 MHz, 500
MHz and 600 MHz instruments, and were calibrated using residual solvent signals as internal references: δH
1
7.26 ppm and δC 77.16 ppm for CDCl3, δH 2.50 ppm and δC 39.52 ppm for DMSO-d6. H NMR data are
reported as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad signal), coupling constants and integration. Proton-decoupled 13C NMR data are
reported in terms of chemical shifts with unresolved signals of chemically distinct carbons indicated.
Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC
experiments. High resolution mass spectra were recorded on a micrOTOF-Q instrument using electrospray
ionization (ESI) in positive or negative ion polarity mode. Analytical thin-layer chromatography was
performed with commercial plates of silica gel 60, visualized with short wavelength UV light (254 nm) and
stained with a p-anisaldehyde solution in EtOH/H2SO4 with subsequent heating. Preparative flash
chromatography was performed with silica gel 60. Reactions that required heating were performed in hot
plate/heating block apparatus with internal temperature control.
General procedure for the synthesis of 4-susbtituted chalcones. To a stirred solution of 4-
substituted benzaldehyde (6 mmol) and acetophenone (0.7 mL, 6 mmol) in absolute ethanol (18 mL), NaOH
(15 M aq solution, 0.6 mL, 9 mmol) was added and the resulting reaction mixture was stirred 20 h at rt.
After completion, the reaction mixture was diluted with absolute ethanol (18 mL) and cooled to 0 °C. The
precipitated product was recovered by filtration, washed with cold absolute ethanol and dried under vacuum.
4-Chlorochalcone was commercially available.
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1
2
3
The Journal of Organic Chemistry
4-Bromochalcone was prepared from 4-bromobenzaldehyde according to the general procedure.
1.33 g (4.63 mmol, 77% yield), pale yellow solid. The spectroscopic data were consistent with those
reported.22
4
5
6
7
8
9
4-t-Butoxychalcone was prepared from 4-t-butoxybenzaldehyde according to the general procedure.
1.63 g (5.81 mmol, 97% yield), pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.05 – 7.98 (m, 2H), 7.79
(d, J = 15.7 Hz, 1H), 7.61 – 7.54 (m, 3H), 7.53 – 7.48 (m, 2H), 7.44 (d, J = 15.7 Hz, 1H), 7.03 (dm, J = 8.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 2H), 1.40 (s, 9H). C{1H} NMR (101 MHz, CDCl3) δ 190.8, 158.3, 144.8, 138.6, 132.8, 129.8, 129.6,
128.7, 128.6, 123.9, 120.8, 79.6, 29.1. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C19H21O2 281.1536,
found 281.1528.
4-Morpholinochalcone was prepared from 4-morpholinobenzaldehyde according to the general
procedure. 1.54 g (5.25 mmol, 87% yield), yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.04 – 7.96 (m, 2H),
7.78 (d, J = 15.6 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.53 – 7.46 (m, 2H), 7.39 (d, J = 15.6 Hz, 1H), 6.92 (dm, J =
8.8 Hz, 2H), 3.91 – 3.84 (m, 4H), 3.31 – 3.25 (m, 4H). C{1H} NMR (101 MHz, CDCl3) δ 190.8, 152.7,
13
145.1, 138.9, 132.6, 130.3, 128.7, 128.5, 126.2, 119.0, 115.0, 66.7, 48.3. HRMS (ESI/Q-TOF) m/z: [M + H]+
calcd for C19H20NO2 294.1494, found 294.1494.
General procedure for the synthesis of 4,6-diaryl-3-cyano-2-pyridones 1a-e-K (Table 1). To a
stirred solution of chalcone (2 mmol) and cyanoacetamide (185 mg, 2.2 mmol) in the indicated alcohol (t-
butyl alcohol or 2-propanol, 24 mL), KOt-Bu (898 mg, 8 mmol) was added in one portion and the resulting
reaction mixture was stirred in open air under the indicated conditions. After completion, 2-propanol (24
mL) was added and the stirring was kept 15 min at rt. The precipitated product was recovered by filtration,
washed with successively 2-propanol (3 x 24 mL), cyclohexane (3 x 12 mL) and Et2O (3 x 12 mL), and
dried under vacuum. The products were characterized as potassium salts. The neutral forms 1a,23,24 1b23,25
and 1c25,26 have been reported.
3-Cyano-4,6-diphenyl-2(1H)-pyridone, potassium salt (1a-K) was prepared from trans-chalcone
according to the general procedure (2-propanol, rt, 60 h). 595 mg (1.92 mmol, 96% yield), pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.97 (dm, J = 6.9 Hz, 2H), 7.57 (dm, J = 6.9 Hz, 2H), 7.51 – 7.32 (m,
6H), 6.53 (s, 1H). C{1H} NMR (101 MHz, DMSO-d6) δ 172.2, 158.9, 154.6, 140.3, 139.3, 128.5, 128.3
13
(2C), 128.2, 128.0, 126.8, 121.5, 101.8, 91.2. HRMS (ESI/Q-TOF) m/z: [M − K]− calcd for C18H11N2O
271.0871, found 271.0871.
4-(4-Chlorophenyl)-3-cyano-6-phenyl-2(1H)-pyridone, potassium salt (1b-K) was prepared from
4-chlorochalcone according to the general procedure (2-propanol, rt, 60 h). 643 mg (1.86 mmol, 93% yield),
1
pale yellow solid. H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.93 (m, 2H), 7.59 (dm, J = 8.6 Hz, 2H), 7.53
(dm, J = 8.6 Hz, 2H), 7.43 – 7.32 (m, 3H), 6.52 (s, 1H). C{1H} NMR (101 MHz, DMSO-d6) δ 172.0,
13
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159.1, 153.3, 140.2, 138.1, 133.1, 129.9, 128.6, 128.4, 128.2, 126.8, 121.3, 101.6, 91.0. HRMS (ESI/Q-
1
2
3
TOF) m/z: [M − K]− calcd for C18H10ClN2O 305.0482, found 305.0477.
4
5
4-(4-Bromophenyl)-3-cyano-6-phenyl-2(1H)-pyridone, potassium salt (1c-K) was prepared from
6
7
4-bromochalcone according to the general procedure (2-propanol, rt, 60 h). 747 mg (1.92 mmol, 96% yield),
1
8
9
pale yellow solid. H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.93 (m, 2H), 7.66 (dm, J = 8.5 Hz, 2H), 7.52
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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(dm, J = 8.5 Hz, 2H), 7.43 – 7.32 (m, 3H), 6.53 (s, 1H). C{1H} NMR (101 MHz, DMSO-d6) δ 172.3,
159.5, 153.8, 140.1, 138.4, 131.6, 130.4, 129.0, 128.5, 127.1, 122.1, 121.2, 102.7, 91.4. HRMS (ESI/Q-
TOF) m/z: [M − K]− calcd for C18H10 79BrN2O 348.9982, found 348.9992 ; calcd for C18H10 81BrN2O
350.9956, found 350.9980.
4-(4-t-Butoxyphenyl)-3-cyano-6-phenyl-2(1H)-pyridone, potassium salt (1d-K) was prepared
from 4-t-butoxychalcone according to the general procedure (2-propanol, rt, 60 h). 589 mg (1.54 mmol, 77%
yield), white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.94 (m, 2H), 7.51 (dm, J = 8.6 Hz, 2H), 7.43 –
7.31 (m, 3H), 7.05 (dm, J = 8.6 Hz, 2H), 6.51 (s, 1H), 1.35 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
172.2, 158.8, 155.4, 154.1, 140.4, 133.7, 128.8, 128.4, 128.1, 126.8, 122.9, 121.7, 101.7, 91.1, 78.3, 28.6.
HRMS (ESI/Q-TOF) m/z: [M − K]− calcd for C22H19N2O2 343.1447, found 343.1443.
3-Cyano-4-(4-morpholinophenyl)-6-phenyl-2(1H)-pyridone, potassium salt (1e-K) was prepared
from 4-morpholinochalcone according to the general procedure (t-butyl alcohol, 30 °C, 48 h). 734 mg (1.86
mmol, 93% yield), pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.01 – 7.91 (m, 2H), 7.49 (d, J = 8.8
Hz, 2H), 7.43 – 7.31 (m, 3H), 7.01 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 3.79 – 3.73 (m, 4H), 3.22 – 3.15 (m,
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4H). C{1H} NMR (101 MHz, DMSO-d6) δ 172.4, 158.7, 154.4, 151.1, 140.5, 129.5, 128.8, 128.4, 128.1,
126.8, 121.9, 114.4, 101.6, 90.9, 66.1, 48.0. HRMS (ESI/Q-TOF) m/z: [M − K]− calcd for C22H18N3O2
356.1405, found 356.1408.
General procedure for the synthesis of 3-acetyl-4,6-diaryl-2-pyridones 2a-e (Scheme 2). To a
stirred suspension of 3-cyano-2-pyridone 1-K (2 mmol) in anhydrous THF (10 mL) under argon
atmosphere, anhydrous 1,4-dioxane (1 mL, 12 mmol) was added and the mixture was cooled to 0 °C. Then,
MeMgBr (3 M solution in Et2O, 4 mL, 12 mmol) was slowly added and the resulting reaction mixture was
stirred 48 h while allowed to reach rt. After completion, 4 mL H2O were added dropwise at 0 °C followed by
14 mL of 1 N aq HCl (14 mmol HCl). The resulting mixture was stirred 12 h at 40 °C. Finally, most of the
THF was evaporated under reduced pressure, an excess volume of 0.1 N aq HCl was added and the product
was extracted with DCM. The combined organic layers were washed with successively 0.1 N aq HCl, H2O
and brine, dried over Na2SO4 and concentrated. The crude product containing 4-8% of the starting 3-cyano-
2-pyridone (neutral form) was precipitated in petroleum ether, recovered by filtration, dried under vacuum
and used without further purification (analytical samples were obtained by flash chromatography on silica
gel).
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3-Acetyl-4,6-diphenyl-2(1H)-pyridone (2a) was prepared from 1a-K according to the general
procedure. 434 mg (1.5 mmol, 75% yield), orange solid. An analytical sample was obtained by flash
chromatography (DCM/EtOAc 85:15 then DCM/EtOAc/EtOH 85:10:5). The spectroscopic data were
consistent with those reported.27
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the general procedure. 440 mg (1.36 mmol, 68% yield), yellowish solid. An analytical sample was obtained
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by flash chromatography (DCM/EtOAc 80:20 then DCM/EtOAc/EtOH 80:15:5). H NMR (500 MHz,
CDCl3) δ 12.36 (br s, 1H), 7.82 – 7.77 (m, 2H), 7.54 – 7.48 (m, 3H), 7.41 (dm, J = 8.5 Hz, 2H), 7.30 (dm, J
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= 8.5 Hz, 2H), 6.54 (s, 1H), 2.43 (s, 3H). C{1H} NMR (126 MHz, CDCl3) δ 202.0, 162.9, 152.6, 148.1,
136.8, 135.4, 132.7, 131.1, 129.42, 129.36, 129.1, 127.8 (br), 127.0, 107.6, 32.0. HRMS (ESI/Q-TOF) m/z:
[M + H]+ calcd for C19H15ClNO2 324.0791, found 324.0792.
3-Acetyl-4-(4-bromophenyl)-6-phenyl-2(1H)-pyridone (2c) was prepared from 1c-K according to
the general procedure. 479 mg (1.30 mmol, 65% yield), yellowish solid. An analytical sample was obtained
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by flash chromatography (DCM/EtOAc 80:20 then DCM/EtOAc/EtOH 80:15:5). H NMR (400 MHz,
DMSO-d6) δ 12.03 (br s, 1H), 7.90 – 7.80 (m, 2H), 7.63 (dm, J = 8.5 Hz, 2H), 7.53 – 7.48 (m, 3H), 7.35
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(dm, J = 8.5 Hz, 2H), 6.62 (br s, 1H), 2.42 (s, 3H). C{1H} NMR (126 MHz, DMSO-d6) δ 202.4, 161.2,
150.2, 148.0 (br), 137.3, 133.0 (br), 131.6, 130.4 (2C), 130.2, 128.9, 127.4, 122.3, 106.7 (br), 31.8. HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C19H15 79BrNO2 368.0286, found 368.0288.
3-Acetyl-4-(4-t-butoxyphenyl)-6-phenyl-2(1H)-pyridone (2d) was prepared from 1d-K according
to the general procedure. 405 mg (1.12 mmol, 56% yield), yellowish solid. An analytical sample was
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obtained by flash chromatography (DCM/EtOAc 80:20 then DCM/EtOAc/EtOH 80:15:5). H NMR (400
MHz, CDCl3) δ 12.90 (br s, 1H), 7.88 – 7.81 (m, 2H), 7.53 – 7.46 (m, 3H), 7.29 (dm, J = 8.6 Hz, 2H), 7.04
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(dm, J = 8.6 Hz, 2H), 6.62 (s, 1H), 2.35 (s, 3H), 1.39 (s, 9H). C{1H} NMR (101 MHz, CDCl3) δ 202.5,
163.2, 156.8, 152.9, 147.6, 133.0, 132.8, 130.8, 129.3, 129.0, 127.8, 127.2, 123.9, 107.8, 79.2, 31.8, 29.0.
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H24NO3 362.1751, found 362.1759.
3-Acetyl-4-(4-morpholinophenyl)-6-phenyl-2(1H)-pyridone (2e) was prepared from 1e-K
according to the general procedure. 454 mg (1.21 mmol, 61% yield), orange solid. An analytical sample was
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obtained by flash chromatography (DCM/EtOAc 70:30 then DCM/EtOAc/EtOH 70:25:5). H NMR (400
MHz, CDCl3) δ 12.58 (br s, 1H), 7.86 – 7.78 (m, 2H), 7.54 – 7.46 (m, 3H), 7.31 (dm, J = 8.8 Hz, 2H), 6.92
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(dm, J = 8.8 Hz, 2H), 6.60 (s, 1H), 3.90 – 3.84 (m, 4H), 3.29 – 3.19 (m, 4H), 2.38 (s, 3H). C{1H} NMR
(101 MHz, CDCl3) δ 202.9, 163.1, 152.8, 151.8, 147.5, 133.1, 130.7, 129.4, 129.3, 128.8, 127.3, 127.1,
115.1, 107.7, 66.9, 48.5, 31.9. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H23N2O3 375.1703, found
375.1692.
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General procedure for the synthesis of 1,3-diketones 3a-e (Scheme 2). 3-Acetyl-2-pyridone 2 (2
mmol) and NaH (60% dispersion in mineral oil, 12 mmol, 480 mg) were suspended in anhydrous 1,4-
dioxane (8 mL) under argon atmosphere, and stirred 1 h at rt. Then, EtOAc (2 mL, 20.5 mmol, see note
below) was added and the resulting reaction mixture was stirred 12 h at rt. After completion, the reaction
was diluted with EtOAc and quenched at 0 °C by slow addition of an excess volume of saturated aq NH4Cl.
The organic layer was separated and the aqueous layer was extracted again with EtOAc. The combined
organic layers were washed with saturated aq NH4Cl, dried over Na2SO4 and concentrated. The product was
isolated by chromatography on silica gel and then precipitated by addition of the indicated solvent.
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Enol/keto ratios were determined by H NMR in CDCl3. Note: commercial grade EtOAc was dried over
CaCl2 overnight, then filtered through a cotton plug and stored over 4 Ȧ molecular sieves until used.
3-Acetoacetyl-4,6-diphenyl-2(1H)-pyridone (3a) was prepared from 2a according to the general
procedure and was isolated by flash chromatography (DCM/EtOAc 85:15 then DCM/EtOAc/EtOH 85:10:5).
557 mg (1.68 mmol, 84% yield), yellowish solid (cyclohexane). Ratio enol/keto 3.6:1. 1H NMR (400 MHz,
CDCl3, enol form) δ 15.41 (br s, 1H), 12.80 (br s, 1H), 7.89 – 7.80 (m, 2H), 7.56 – 7.36 (m, 8H), 6.63 (s,
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1H), 5.86 (s, 1H), 2.02 (s, 3H). H NMR (400 MHz, CDCl3, keto form) δ 12.80 (br s, 1H), 7.89 – 7.80 (m,
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2H), 7.56 – 7.36 (m, 8H), 6.60 (s, 1H), 3.96 (s, 2H), 2.00 (s, 3H). C{1H} NMR (101 MHz, CDCl3, enol
form) δ 191.4, 184.9, 163.1, 154.9, 147.8, 139.0, 132.9, 130.9, 129.3, 129.0 (2C), 128.7, 127.9, 127.2, 108.1,
104.2, 25.3. HRMS (ESI/Q-TOF) m/z: [M − H]− calcd for C21H16NO3 330.1130, found 330.1123.
3-Acetoacetyl-4-(4-chlorophenyl)-6-phenyl-2(1H)-pyridone (3b) was prepared from 3b according
to the general procedure and was isolated by flash chromatography (DCM/EtOAc 80:20 then
DCM/EtOAc/EtOH 80:15:5). 578 mg (1.58 mmol, 79% yield), yellowish solid (cyclohexane). Ratio
enol/keto 3.7:1. 1H NMR (400 MHz, CDCl3, enol form) δ 15.40 (br s, 1H), 12.60 (br s, 1H), 7.86 – 7.76 (m,
2H), 7.55 – 7.45 (m, 3H), 7.43 – 7.32 (m, 4H), 6.56 (s, 1H), 5.90 (s, 1H), 2.05 (s, 3H). 1H NMR (400 MHz,
CDCl3, keto form) δ 12.60 (br s, 1H), 7.86 – 7.76 (m, 2H), 7.55 – 7.45 (m, 3H), 7.43 – 7.32 (m, 4H), 6.53 (s,
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1H), 4.00 (s, 2H), 2.00 (s, 3H). C{1H} NMR (101 MHz, CDCl3, enol form) δ 191.6, 184.5, 162.9, 153.7,
148.0, 137.4, 135.2, 132.7, 131.0, 129.4, 129.3, 129.0, 127.4, 127.1, 107.7, 104.1, 25.4. HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C21H17ClNO3 366.0897, found 366.0894.
3-Acetoacetyl-4-(4-bromophenyl)-6-phenyl-2(1H)-pyridone (3c) was prepared from 2c according
to the general procedure and was isolated by flash chromatography (DCM/EtOAc 80:20 then
DCM/EtOAc/EtOH 80:15:5). 591 mg (1.44 mmol, 72% yield), yellowish solid (cyclohexane). Ratio
enol/keto 3.4:1. 1H NMR (400 MHz, CDCl3, enol form) δ 15.38 (br s, 1H), 11.94 (br s, 1H), 7.82 – 7.73 (m,
2H), 7.55 (dm, J = 8.5 Hz, 2H), 7.58 – 7.46 (m, 3H), 7.30 (dm, J = 8.5 Hz, 2H), 6.55 (s, 1H), 5.89 (s, 1H),
2.05 (s, 3H). 1H NMR (400 MHz, CDCl3, keto form) δ 11.94 (br s, 1H), 7.82 – 7.73 (m, 2H), 7.58 – 7.46 (m,
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5H), 7.33 – 7.24 (m, 2H), 6.51 (s, 1H), 4.01 (s, 2H), 2.04 (s, 3H). C{1H} NMR (101 MHz, CDCl3, enol
form) δ 191.7, 184.5, 162.6, 153.7, 147.9, 137.9, 132.7, 131.9, 131.1, 129.51, 129.48, 127.2, 127.0, 123.5,
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The Journal of Organic Chemistry
107.6, 104.1, 25.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C21H17 79BrNO3 410.0386, found 410.0388
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3-Acetoacetyl-4-(4-t-butoxyphenyl)-6-phenyl-2(1H)-pyridone (3d) was prepared from 2d
according to the general procedure and was isolated by flash chromatography (DCM/EtOAc 80:20 then
DCM/EtOAc/EtOH 80:15:5). 670 mg (1.66 mmol, 83% yield), yellowish solid (cyclohexane). Ratio
enol/keto 3.8:1. 1H NMR (400 MHz, CDCl3, enol form) δ 15.43 (br s, 1H), 12.58 (br s, 1H), 7.87 – 7.80 (m,
2H), 7.53 – 7.44 (m, 3H), 7.34 (dm, J = 8.6 Hz, 2H), 7.01 (dm, J = 8.6 Hz, 2H), 6.63 (s, 1H), 5.72 (s, 1H),
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1.99 (s, 3H), 1.39 (s, 9H). H NMR (400 MHz, CDCl3, keto form) δ 12.58 (br s, 1H), 7.87 – 7.80 (m, 2H),
7.53 – 7.44 (m, 3H), 7.31 (dm, J = 8.6 Hz, 2H), 7.01 (dm, J = 8.6 Hz, 2H), 6.60 (s, 1H), 3.90 (s, 2H), 2.02
(s, 3H), 1.39 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3, enol form) δ 191.3, 185.4, 163.0, 156.6, 154.2,
147.7, 133.4, 133.0, 130.8, 129.3 (2C), 128.9, 127.1, 123.8, 107.9, 104.1, 79.2, 29.0, 25.3. HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C25H26NO4 404.1862, found 404.1859.
3-Acetoacetyl-4-(4-morpholinophenyl)-6-phenyl-2(1H)-pyridone (3e) was prepared from 2e
according to the general procedure and was isolated by flash chromatography (DCM/EtOAc 70:30 then
DCM/EtOAc/EtOH 70:25:5). 624 mg (1.50 mmol, 75% yield), orange solid (cyclohexane). Ratio enol/keto
3.9:1. 1H NMR (400 MHz, CDCl3, enol form) δ 15.49 (br s, 1H), 12.56 (br s, 1H), 7.85 – 7.78 (m, 2H), 7.52
– 7.44 (m, 3H), 7.38 (dm, J = 8.8 Hz, 2H), 6.91 (dm, J = 8.8 Hz, 2H), 6.62 (s, 1H), 5.85 (s, 1H), 3.91 – 3.83
(m, 4H), 3.31 – 3.19 (m, 4H), 2.05 (s, 3H). 1H NMR (400 MHz, CDCl3, keto form) δ 12.56 (br s, 1H), 7.85 –
7.78 (m, 2H), 7.52 – 7.44 (m, 3H), 7.33 (dm, J = 8.8 Hz, 2H), 6.91 (dm, J = 8.8 Hz, 2H), 6.59 (s, 1H), 3.93
(s, 2H), 3.91 – 3.83 (m, 4H), 3.31 – 3.19 (m, 4H), 2.04 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3, enol form)
δ 191.5, 185.7, 163.1, 154.2, 151.7, 147.4, 133.0, 130.7, 129.32, 129.28, 129.24, 127.1, 122.3, 114.9, 107.8,
104.2, 66.9, 48.5, 25.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C25H25N2O4 417.1809, found
417.1808.
2-Methyl-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (5a) (Scheme 3). 1,3-Diketone 3a (33 mg,
0.1 mmol) was dissolved in H2SO4 (1 mL) and the resulting mixture was stirred 1 h at rt. The reaction
mixture was then diluted with chloroform (3 mL), cooled to 0 °C, and quenched under vigorous stirring by
dropwise addition of an excess volume of cold H2O. The organic layer was separated and the aqueous layer
was extracted again with chloroform. The combined organic layers were washed with successively H2O, aq
NaHCO3 and brine, then dried over Na2SO4 and concentrated. The product was isolated by flash
chromatography on silica gel (DCM/EtOAc 97:3). 28 mg (0.089 mmol, 89% yield), white solid
(cyclohexane). 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.08 (m, 2H), 7.66 (s, 1H), 7.55 – 7.48 (m, 3H), 7.48 –
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7.42 (m, 3H), 7.42 – 7.36 (m, 2H), 6.10 (d, J = 0.5 Hz, 1H), 2.45 (d, J = 0.5 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 178.3, 165.1, 162.2, 159.1, 154.6, 139.1, 137.0, 130.8, 129.1, 128.41, 128.38, 127.9, 127.8,
121.6, 114.1, 112.3, 20.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C21H16NO2 314.1181, found
314.1180.
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General procedure for the synthesis of 2-(methylthio)-azachromones 4a-e (Scheme 4). To a
suspension of 1,3-diketone 3 (1 mmol) in anhydrous acetonitrile (10 mL) under argon atmosphere, DBU
(0.33 mL, 2.2 mmol) was added and the resulting mixture was stirred 30 min at rt while the starting diketone
dissolved. Then, carbon disulfide (0.54 mL, 9 mmol) was first added, followed after 4 h by dimethyl sulfate
(0.21 mL, 2.2 mmol). The reaction mixture was stirred 12 h at rt while product 4 slowly precipitated. After
completion, 10 mL acetonitrile and 20 mL H2O were added, resulting in the complete precipitation of the
product. After 15 min of additional stirring, the product was recovered by filtration, washed with
successively H2O/acetonitrile mixture (1:1 v/v) and petroleum ether, and dried under vacuum.
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3-Acetyl-2-(methylthio)-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (4a) was prepared from 3a
according to the general procedure. 353 mg (0.91 mmol, 91% yield), pale yellow solid. 1H NMR (400 MHz,
CDCl3) δ 8.17 – 8.11 (m, 2H), 7.69 (s, 1H), 7.56 – 7.44 (m, 6H), 7.43 – 7.37 (m, 2H), 2.71 (s, 3H), 2.58 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.9, 177.4, 174.6, 160.8, 159.0, 155.3, 139.0, 136.7, 131.1,
129.2, 128.7, 128.3, 128.1, 127.8, 122.6, 119.9, 114.2, 32.2, 14.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd
for C23H18NO3S 388.1007, found 388.1008.
3-Acetyl-5-(4-chlorophenyl)-2-(methylthio)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one (4b) was
prepared from 3b according to the general procedure. 367 mg (0.87 mmol, 87% yield), pale yellow solid. 1H
NMR (400 MHz, CDCl3) δ 8.19 – 8.08 (m, 2H), 7.65 (s, 1H), 7.58 – 7.49 (m, 3H), 7.45 (dm, J = 8.5 Hz,
2H), 7.34 (dm, J = 8.5 Hz, 2H), 2.71 (s, 3H), 2.58 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.8, 177.6,
174.6, 160.8, 159.3, 154.0, 137.4, 136.6, 134.9, 131.2, 129.7, 129.3, 128.5, 127.8, 122.4, 119.8, 114.1, 32.2,
14.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H17ClNO3S 422.0612, found 422.0619.
3-Acetyl-5-(4-bromophenyl)-2-(methylthio)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one (4c) was
prepared from 3c according to the general procedure. 410 mg (0.88 mmol, 88% yield), pale yellow solid. 1H
NMR (400 MHz, CDCl3) δ 8.16 – 8.09 (m, 2H), 7.65 (s, 1H), 7.60 (dm, J = 8.5 Hz, 2H), 7.55 – 7.50 (m,
3H), 7.28 (dm, J = 8.5 Hz, 2H), 2.71 (s, 3H), 2.57 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.7, 177.6,
174.5, 160.8, 159.3, 154.0, 137.9, 136.5, 131.4, 131.2, 130.0, 129.2, 127.8, 123.1, 122.3, 119.8, 114.0, 32.2,
14.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H17 79BrNO3S 466.0107, found 466.0119 ; calcd for
C23H17 81BrNO3S 468.0092, found 468.0103.
3-Acetyl-5-(4-t-butoxyphenyl)-2-(methylthio)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one (4d) was
prepared from 3d according to the general procedure. 409 mg (0.89 mmol, 89% yield), pale yellow solid. 1H
NMR (400 MHz, CDCl3) δ 8.18 – 8.10 (m, 2H), 7.70 (s, 1H), 7.56 – 7.48 (m, 3H), 7.33 (dm, J = 8.6 Hz,
2H), 7.08 (dm, J = 8.6 Hz, 2H), 2.71 (s, 3H), 2.59 (s, 3H), 1.45 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
197.9, 177.1, 174.7, 160.9, 158.9, 156.4, 155.1, 136.8, 133.2, 131.0, 129.4, 129.2, 127.8, 123.0, 122.7,
119.9, 114.2, 79.0, 32.1, 29.1, 14.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C27H26NO4S 460.1577,
found 460.1591.
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3-Acetyl-2-(methylthio)-5-(4-morpholinophenyl)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one (4e)
was prepared from 3e according to the general procedure. 421 mg (0.89 mmol, 89% yield), yellowish solid.
1H NMR (400 MHz, CDCl3) δ 8.16 – 8.08 (m, 2H), 7.69 (s, 1H), 7.57 – 7.47 (m, 3H), 7.38 (dm, J = 8.7 Hz,
2H), 6.98 (dm, J = 8.7 Hz, 2H), 3.95 – 3.82 (m, 4H), 3.36 – 3.21 (m, 4H), 2.71 (s, 3H), 2.61 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 198.0, 177.1, 175.0, 161.1, 158.8, 155.1, 151.5, 136.9, 130.9, 130.0,
129.3, 129.2, 127.7, 122.5, 119.9, 114.4, 114.0, 67.0, 48.5, 32.3, 14.6. HRMS (ESI/Q-TOF) m/z: [M + H]+
calcd for C27H25N2O4S 473.1530, found 473.1528.
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General procedures for the synthesis of 2-(substituted amino)-8-azachromones 6aa-am, 6ba-bc,
6ca-cc, 6da-db and 6ea-eb (Table 2 and Scheme 7). Note: safety precautions must be taken due to the
release of toxic methanethiol. Procedure A: 2-(Methylthio)-8-azachromone 4 (0.1 mmol) and amine
(amount indicated) were dissolved in anhydrous DCM (volume indicated) under argon atmosphere, and the
resulting mixture was stirred under the indicated conditions. After completion, the crude reaction mixture
was applied on top of a silica gel column and the product was eluted with the indicated solvent. Procedure
B: 2-(Methylthio)-8-azachromone 4 (0.1 mmol), amine (0.11 mmol) and DMAP (4 mg, 0.03 mmol) were
dissolved in the indicated anhydrous solvent (THF or 1,4-dioxane, 2 mL), and the resulting mixture was
stirred in open air under the indicated conditions. After completion, the reaction mixture was cooled to rt
and the product was precipitated by addition of the indicated solvents. After 15 min of additional stirring,
the product was recovered by filtration, washed with the indicated solvents, and dried under vacuum.
3-Acetyl-5,7-diphenyl-2-(piperidin-1-yl)-4H-pyrano[2,3-b]pyridin-4-one (6aa) was prepared from
4a and piperidine (11 μL, 0.11 mmol) according to procedure A (1 mL DCM, rt, 12 h), and was eluted with
1
DCM/EtOAc 85:15. 41 mg (0.096 mmol, 96% yield), white solid (cyclohexane). H NMR (400 MHz,
CDCl3) δ 8.11 – 8.06 (m, 2H), 7.57 (s, 1H), 7.54 – 7.37 (m, 8H), 3.56 – 3.49 (m, 4H), 2.54 (s, 3H), 1.83 –
13
1.70 (m, 6H). C{1H} NMR (101 MHz, CDCl3) δ 197.9, 176.7, 163.3, 158.5, 158.2, 154.6, 139.8, 137.3,
130.5, 129.1, 128.34, 128.29, 127.9, 127.6, 121.8, 114.0, 103.8, 50.3, 33.0, 26.0, 23.9. HRMS (ESI/Q-TOF)
m/z: [M + H]+ calcd for C27H25N2O3 425.1860, found 425.1877.
3-Acetyl-2-morpholino-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (6ab) was prepared from 4a
and morpholine (10 μL, 0.11 mmol) according to procedure A (1 mL DCM, rt, 12 h), and was eluted with
DCM/EtOAc 4:1. 40 mg (0.093 mmol, 93% yield), white solid (cyclohexane). 1H NMR (400 MHz, CDCl3)
δ 8.15 – 8.01 (m, 2H), 7.60 (s, 1H), 7.54 – 7.37 (m, 8H), 3.93 – 3.82 (m, 4H), 3.65 – 3.54 (m, 4H), 2.54 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.9, 176.8, 163.0, 158.4 (2C), 154.7, 139.5, 137.1, 130.6, 129.1,
128.4, 128.3, 128.0, 127.6, 122.0, 113.9, 104.1, 66.5, 49.3, 33.1. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd
for C26H23N2O4 427.1652, found 427.1665.
3-Acetyl-2-(methylamino)-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (6ac) was prepared from
4a and methylamine (8.03 M solution in absolute ethanol, 14 μL, 0.11 mmol) according to procedure A (1
mL DCM, rt, 12 h), and was eluted with DCM/EtOAc 19:1. 36 mg (0.097 mmol, 97% yield), white solid
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(cyclohexane). H NMR (400 MHz, CDCl3) δ 11.49 (br q, 1H), 8.16 – 8.04 (m, 2H), 7.61 (s, 1H), 7.55 –
7.43 (m, 6H), 7.42 – 7.35 (m, 2H), 3.31 (d, J = 5.1 Hz, 3H), 2.59 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 199.8, 175.3, 165.8, 158.03, 157.97, 155.2, 139.9, 137.0, 130.7, 129.1, 128.3, 128.2, 128.0, 127.6, 122.4,
114.0, 100.2, 32.6, 28.0. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H19N2O3 371.1390, found
371.1409.
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3-Acetyl-2-(benzylamino)-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (6ad) was prepared from
4a and benzylamine (12 μL, 0.11 mmol) according to procedure A (1 mL DCM, rt, 12 h), and was eluted
1
with DCM/EtOAc 19:1. 42 mg (0.094 mmol, 94% yield), white solid (cyclohexane). H NMR (400 MHz,
CDCl3) δ 11.91 (br t, J = 5.4 Hz, 1H), 8.17 – 8.05 (m, 2H), 7.61 (s, 1H), 7.55 – 7.37 (m, 12H), 7.37 – 7.32
13
(m, 1H), 4.91 (d, J = 5.8 Hz, 2H), 2.60 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 199.8, 175.4, 164.9,
158.0, 157.9, 155.1, 139.9, 137.0, 136.3, 130.7, 129.16, 129.13, 128.3, 128.23, 128.19, 127.98, 127.95,
127.6, 122.4, 114.0, 100.1, 45.5, 32.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C29H23N2O3 447.1709,
found 447.1710.
3-Acetyl-2-(2-hydroxyethylamino)-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one
(6ae)
was
prepared from 4a and ethanolamine (7 μL, 0.11 mmol) according to procedure A (1 mL DCM, rt, 12 h).
After completion, the precipitated product was recovered by filtration and washed with DCM. 26 mg (0.065
mmol, 65% yield), white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br t, 1H), 8.25 – 8.19 (m, 2H), 7.80
(s, 1H), 7.58 – 7.50 (m, 3H), 7.42 (br s, 5H), 5.13 (t, J = 4.6 Hz, 1H), 3.76 – 3.66 (m, 4H), 2.41 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 197.4, 174.7, 164.4, 157.5, 156.7, 154.2, 139.6, 136.2, 130.8, 129.1,
128.5, 127.8, 127.54, 127.45, 121.6, 113.5, 99.3, 59.2, 43.5, 32.1. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd
for C24H21N2O4 401.1501, found 401.1498.
Methyl 2-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)acetate (6af) was
prepared from 4a according to procedure A (1 mL DCM, rt, 12 h) using glycine methyl ester hydrochloride
(19 mg, 0.15 mmol) and triethylamine (15 μL, 0.11 mmol), and was eluted with DCM/EtOAc 9:1. 27 mg
(0.063 mmol, 63% yield), white solid (cyclohexane). 1H NMR (400 MHz, CDCl3) δ 11.88 (br t, J = 5.3 Hz,
1H), 8.12 – 8.05 (m, 2H), 7.61 (s, 1H), 7.55 – 7.43 (m, 6H), 7.42 – 7.35 (m, 2H), 4.51 (d, J = 5.6 Hz, 2H),
13
3.87 (s, 3H), 2.62 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 200.0, 175.3, 168.7, 165.2, 158.2, 157.8,
155.2, 139.7, 136.9, 130.8, 129.2, 128.4, 128.2, 128.0, 127.6, 122.5, 114.1, 100.4, 53.0, 43.0, 32.6. HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C25H21N2O5 429.1445, found 429.1437.
3-Acetyl-2-(4-methoxyphenylamino)-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-4-one (6ag) was
prepared from 4a and p-anisidine according to procedure B (2 mL THF, 65 °C, 2 h). The product was
precipitated by addition of cyclohexane (4 mL), recovered by filtration, and washed with cyclohexane/THF
2:1 and petroleum ether. 42 mg (0.091 mmol, 91% yield), white solid. 1H NMR (400 MHz, CDCl3) δ 13.49
(s, 1H), 8.13 – 8.06 (m, 2H), 7.63 (s, 1H), 7.53 (dm, J = 9.0 Hz, 2H), 7.51 – 7.45 (m, 6H), 7.44 – 7.38 (m,
2H), 7.02 (dm, J = 9.0 Hz, 2H), 3.88 (s, 3H), 2.67 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 200.1, 175.5,
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162.6, 158.2, 158.1, 157.9, 155.0, 139.8, 136.8, 130.8, 129.1, 128.40, 128.36, 128.2, 128.0, 127.6, 124.8,
122.3, 114.8, 114.1, 100.1, 55.7, 32.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C29H23N2O4 463.1652,
found 463.1643.
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3-Acetyl-5,7-diphenyl-2-(phenylamino)-4H-pyrano[2,3-b]pyridin-4-one (6ah) was prepared from
4a and aniline according to procedure B (2 mL THF, 65 °C, 2 h). The product was precipitated by addition
of cyclohexane (4 mL), recovered by filtration, and washed with cyclohexane/THF 2:1 and petroleum ether.
39 mg (0.09 mmol, 90% yield), pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 13.61 (s, 1H), 8.15 – 8.08
(m, 2H), 7.67 – 7.61 (m, 2H), 7.64 (s, 1H), 7.54 – 7.46 (m, 8H), 7.44 – 7.38 (m, 2H), 7.32 (tm, J = 7.4 Hz,
1H), 2.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 200.3, 175.6, 162.8, 158.3, 157.9, 155.0, 139.7,
136.8, 135.8, 130.8, 129.7, 129.1, 128.4, 128.2, 128.0, 127.7, 126.4, 123.2, 122.4, 114.2, 100.3, 32.8. HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C28H21N2O3 433.1547, found 433.1551.
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Ethyl 4-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)benzoate (6ai) was
prepared from 4a and ethyl 4-aminobenzoate according to procedure B (2 mL dioxane, 100 °C, 36 h). The
product was precipitated by addition of dioxane (2 mL) and cyclohexane (8 mL), recovered by filtration, and
washed with cyclohexane/dioxane 2:1 and petroleum ether. 31 mg (0.061 mmol, 61% yield), white solid. 1H
NMR (400 MHz, CDCl3) δ 13.80 (s, 1H), 8.18 (dm, J = 8.7 Hz, 2H), 8.16 – 8.11 (m, 2H), 7.74 (dm, J = 8.7
Hz, 2H), 7.67 (s, 1H), 7.56 – 7.45 (m, 6H), 7.44 – 7.38 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.43
13
(t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 200.7, 175.5, 166.0, 162.7, 158.5, 157.8, 155.1,
139.8, 139.5, 136.6, 131.3, 131.0, 129.2, 128.5, 128.2, 128.1, 127.8, 127.7, 122.5, 122.3, 114.1, 100.7, 61.3,
32.8, 14.5. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C31H25N2O5 505.1758, found 505.1732.
(S)-Methyl
2-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)-3-
phenylpropanoate (6aj) was prepared from 4a according to procedure A (1 mL DCM, rt, 84 h) using L-
phenylalanine methyl ester hydrochloride (32 mg, 0.15 mmol) and triethylamine (15 μL, 0.11 mmol), and
20
was eluted with DCM/EtOAc 49:1. 37 mg (0.071 mmol, 71% yield), white solid (MeOH).
+13.2° (c
[ ]
α
D
1
1.0, CHCl3). H NMR (500 MHz, CDCl3) δ 11.91 (d, J = 7.8 Hz, 1H), 8.11 – 8.05 (m, 2H), 7.58 (s, 1H),
7.55 – 7.42 (m, 6H), 7.39 – 7.28 (m, 6H), 7.25 – 7.20 (m, 1H), 5.21 (td, J = 8.0, 5.0 Hz, 1H), 3.83 (s, 3H),
13
3.41 (dd, J = 13.9, 5.0 Hz, 1H), 3.24 (dd, J = 13.9, 8.1 Hz, 1H), 2.58 (s, 3H). C{1H} NMR (126 MHz,
CDCl3) δ 199.8, 175.3, 170.6, 164.6, 157.9, 157.6, 155.0, 139.7, 136.9, 135.4, 130.7, 129.5, 129.1, 129.0,
128.3, 128.2, 128.0, 127.60, 127.55, 122.3, 113.9, 100.2, 56.0, 53.1, 39.0, 32.7. HRMS (ESI/Q-TOF) m/z:
[M + H]+ calcd for C32H27N2O5 519.1914, found 519.1915.
(S)-Methyl
2-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)-3-(4-
hydroxyphenyl)propanoate (6ak) was prepared from 4a according to procedure A (1 mL DCM, rt, 84 h)
using L-tyrosine methyl ester hydrochloride (35 mg, 0.15 mmol) and triethylamine (15 μL, 0.11 mmol), and
[ ]20
was eluted with DCM/EtOAc 85:15. 40 mg (0.075 mmol, 75% yield), white solid (cyclohexane).
α
D
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+29.8° (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 11.80 (d, J = 7.8 Hz, 1H), 8.12 – 8.03 (m, 2H), 7.59
(s, 1H), 7.54 – 7.48 (m, 3H), 7.47 – 7.41 (m, 3H), 7.39 – 7.33 (m, 2H), 7.11 (dm, J = 8.5 Hz, 2H), 6.72 (dm,
J = 8.5 Hz, 2H), 5.93 (br s, 1H), 5.17 (td, J = 7.7, 4.9 Hz, 1H), 3.82 (s, 3H), 3.31 (dd, J = 14.1, 4.9 Hz, 1H),
3.18 (dd, J = 14.1, 7.7 Hz, 1H), 2.58 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 200.2, 175.4, 170.7, 164.6,
158.1, 157.7, 155.6, 155.1, 139.7, 136.9, 130.8, 130.7, 129.2, 128.4, 128.2, 128.0, 127.6, 126.8, 122.5,
115.9, 113.9, 100.3, 56.2, 53.1, 38.0, 32.5. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C32H27N2O6
535.1864, found 535.1864.
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(S)-Methyl 2-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)-3-(1H-indol-3-
yl)propanoate (6al) was prepared from 4a according to procedure A (1 mL DCM, rt, 60 h) using L-
tryptophan methyl ester hydrochloride (38 mg, 0.15 mmol) and triethylamine (15 μL, 0.11 mmol), and was
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eluted with DCM/EtOAc 9:1. 45 mg (0.081 mmol, 81% yield), pale yellow solid (MeOH).
−19.8° (c
[ ]
α
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 11.88 (d, J = 7.5 Hz, 1H), 8.20 (br s, 1H), 8.11 – 8.04 (m, 2H),
7.71 – 7.67 (m, 1H), 7.57 (s, 1H), 7.54 – 7.48 (m, 3H), 7.48 – 7.42 (m, 3H), 7.38 – 7.33 (m, 2H), 7.33 – 7.29
(m, 1H), 7.23 (br d, J = 2.4 Hz, 1H), 7.20 – 7.12 (m, 2H), 5.26 (td, J = 7.3, 5.2 Hz, 1H), 3.78 (s, 3H), 3.55
(dd, J = 14.8, 5.2 Hz, 1H), 3.49 (dd, J = 14.8, 7.2 Hz, 1H), 2.57 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
199.8, 175.4, 171.1, 164.7, 157.9, 157.7, 155.0, 139.8, 136.9, 136.4, 130.7, 129.1, 128.3, 128.2, 128.0,
127.6, 127.1, 123.7, 122.5, 122.2, 119.9, 118.7, 113.9, 111.5, 109.4, 100.3, 55.3, 53.1, 32.6, 28.9. HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C34H28N3O5 558.2023, found 558.2017.
(S)-Methyl 2-(3-acetyl-4-oxo-5,7-diphenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)-3-(1H-imidazol-
4-yl)propanoate (6am) was prepared from 4a according to procedure A (1 mL DCM, rt, 72 h) using L-
histidine methyl ester dihydrochloride (29 mg, 0.12 mmol) and triethylamine (28 μL, 0.2 mmol), and was
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eluted with DCM/EtOH 93:7. 22 mg (0.043 mmol, 43% yield), yellowish solid (Et O).
−3.4° (c 0.5,
[ ]
α
2
D
CHCl3). 1H NMR (400 MHz, CDCl3) δ 11.85 (d, J = 7.6 Hz, 1H), 8.09 – 8.03 (m, 2H), 7.56 – 7.53 (m, 2H),
7.52 – 7.34 (m, 9H), 6.93 (s, 1H), 5.30 – 5.22 (m, 1H), 3.84 (s, 3H), 3.38 (dd, J = 15.0, 5.9 Hz, 1H), 3.30
13
(dd, J = 15.0, 4.9 Hz, 1H), 2.55 (s, 3H). C{1H} NMR (151 MHz, CDCl3) δ 199.8, 175.5, 170.7, 164.6,
158.1, 157.8, 155.1, 139.7, 136.8, 135.6, 130.8, 129.1, 128.4 (2C), 128.2 (2C), 128.0, 127.6, 122.4, 113.9,
100.4, 54.6, 53.2, 32.6, 30.5. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C29H25N4O5 509.1819, found
509.1825.
3-Acetyl-2-(benzylamino)-5-(4-chlorophenyl)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one
(6ba)
was prepared from 4b and benzylamine (12 μL, 0.11 mmol) according to procedure A (2 mL DCM, rt, 24
1
h), and was eluted with DCM/EtOAc 49:1. 47 mg (0.098 mmol, 98% yield), white solid (DCM). H NMR
(400 MHz, CDCl3) δ 11.93 (br t, J = 5.5 Hz, 1H), 8.14 – 8.07 (m, 2H), 7.57 (s, 1H), 7.55 – 7.49 (m, 3H),
7.48 – 7.38 (m, 6H), 7.37 – 7.30 (m, 3H), 4.91 (d, J = 5.8 Hz, 2H), 2.60 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 199.8, 175.3, 164.9, 158.3, 157.9, 153.8, 138.2, 136.8, 136.3, 134.5, 130.8, 129.6, 129.2 (2C),
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128.3 (2C), 128.0, 127.6, 122.2, 113.9, 100.1, 45.5, 32.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
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2
3
C29H22ClN2O3 481.1313, found 481.1308.
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(S)-Methyl 2-(3-acetyl-5-(4-chlorophenyl)-4-oxo-7-phenyl-4H-pyrano[2,3-b]pyridin-2-ylamino)-
3-(4-hydroxyphenyl)propanoate (6bb) was prepared from 4b according to procedure A (2 mL DCM, rt,
120 h) using L-tyrosine methyl ester hydrochloride (35 mg, 0.15 mmol) and triethylamine (15 μL, 0.11
mmol), and was eluted with DCM/EtOAc 8:1. 42 mg (0.074 mmol, 74% yield), white solid (cyclohexane).
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[ ]20
+33.7° (c 0.5, DMSO). 1H NMR (400 MHz, CDCl3) δ 11.84 (d, J = 7.8 Hz, 1H), 8.11 – 8.04 (m, 2H),
α
D
7.54 (s, 1H), 7.53 – 7.49 (m, 3H), 7.41 (dm, J = 8.5 Hz, 2H), 7.29 (dm, J = 8.5 Hz, 2H), 7.12 (dm, J = 8.5
Hz, 2H), 6.74 (dm, J = 8.5 Hz, 2H), 5.49 (br s, 1H), 5.16 (td, J = 7.8, 4.9 Hz, 1H), 3.82 (s, 3H), 3.32 (dd, J =
14.1, 4.9 Hz, 1H), 3.18 (dd, J = 14.1, 7.8 Hz, 1H), 2.58 (s, 3H). 1H NMR (400 MHz, DMSO-d6) δ 11.55 (d,
J = 7.3 Hz, 1H), 9.30 (s, 1H), 8.25 – 8.19 (m, 2H), 7.83 (s, 1H), 7.59 – 7.52 (m, 3H), 7.49 (dm, J = 8.7 Hz,
2H), 7.44 (dm, J = 8.7 Hz, 2H), 7.06 (dm, J = 8.5 Hz, 2H), 6.68 (dm, J = 8.5 Hz, 2H), 5.13 – 5.07 (m, 1H),
13
3.77 (s, 3H), 3.23 (dd, J = 14.1, 5.5 Hz, 1H), 3.17 (dd, J = 14.1, 6.6 Hz, 1H), 2.40 (s, 3H). C{1H} NMR
(101 MHz, DMSO-d6) δ 197.8, 174.6, 170.3, 163.9, 157.1, 156.9, 156.5, 152.8, 138.2, 136.0, 132.7, 130.8,
130.4, 130.3, 129.1, 127.46, 127.42, 125.4, 121.6, 115.3, 113.4, 99.4, 55.6, 52.7, 36.8, 31.9. HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C32H26ClN2O6 569.1479, found 569.1479.
Ethyl
4-(3-acetyl-5-(4-chlorophenyl)-4-oxo-7-phenyl-4H-pyrano[2,3-b]pyridin-2-
ylamino)benzoate (6bc) was prepared from 4b and ethyl 4-aminobenzoate according to procedure B (2 mL
dioxane, 100 °C, 36 h). The product was precipitated by addition of dioxane (2 mL) and cyclohexane (4
mL), recovered by filtration, and washed with cyclohexane/dioxane 1:1 and petroleum ether. 33 mg (0.061
mmol, 61% yield), white solid. 1H NMR (400 MHz, CDCl3) δ 13.81 (s, 1H), 8.18 (dm, J = 8.7 Hz, 2H), 8.15
– 8.09 (m, 2H), 7.73 (dm, J = 8.7 Hz, 2H), 7.62 (s, 1H), 7.55 – 7.50 (m, 3H), 7.45 (dm, J = 8.5 Hz, 2H), 7.34
13
(dm, J = 8.5 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). C{1H} NMR (101
MHz, CDCl3) δ 200.6, 175.5, 166.0, 162.7, 158.7, 157.8, 153.8, 139.7, 137.9, 136.4, 134.7, 131.3, 131.1,
129.6, 129.2, 128.4, 128.0, 127.7, 122.3 (2C), 114.0, 100.7, 61.3, 32.9, 14.5. HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C31H24ClN2O5 539.1368, found 539.1370.
3-Acetyl-5-(4-bromophenyl)-2-(methylamino)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one
(6ca)
was prepared from 4c and methylamine (8.03 M solution in absolute ethanol, 14 μL, 0.11 mmol) according
to procedure A (2 mL DCM, rt, 24 h), and was eluted with DCM/EtOAc 24:1. 41 mg (0.091 mmol, 91%
1
yield), pale yellow solid (cyclohexane). H NMR (400 MHz, CDCl3) δ 11.51 (br q, 1H), 8.13 – 8.06 (m,
2H), 7.58 (dm, J = 8.5 Hz, 2H), 7.56 (s, 1H), 7.54 – 7.47 (m, 3H), 7.26 (dm, J = 8.5 Hz, 2H), 3.31 (d, J = 5.1
13
Hz, 3H), 2.60 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 199.7, 175.2, 165.8, 158.3, 158.0, 153.8, 138.8,
136.9, 131.2, 130.8, 129.9, 129.2, 127.6, 122.7, 122.1, 113.8, 100.1, 32.7, 28.1. HRMS (ESI/Q-TOF) m/z:
[M + H]+ calcd for C23H18 79BrN2O3 449.0495, found 449.0496 ; calcd for C23H18 81BrN2O3 451.0481, found
451.0479.
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3-Acetyl-2-(benzylamino)-5-(4-bromophenyl)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one
(6cb)
1
2
3
4
was prepared from 4c and benzylamine (12 μL, 0.11 mmol) according to procedure A (2 mL DCM, rt, 24 h),
1
and was eluted with DCM/EtOAc 99:1. 47 mg (0.089 mmol, 89% yield), white solid (cyclohexane). H
5
6
7
8
NMR (400 MHz, CDCl3) δ 11.93 (br t, J = 5.6 Hz, 1H), 8.13 – 8.07 (m, 2H), 7.58 (dm, J = 8.5 Hz, 2H), 7.57
(s, 1H), 7.54 – 7.49 (m, 3H), 7.47 – 7.38 (m, 4H), 7.34 (tm, J = 7.1 Hz, 1H), 7.26 (dm, J = 8.5 Hz, 2H), 4.91
13
9
(d, J = 5.8 Hz, 2H), 2.60 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 199.8, 175.3, 164.9, 158.3, 157.9,
10
11
12
13
14
15
16
17
18
19
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26
27
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29
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31
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36
37
38
39
40
41
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43
44
45
46
47
48
49
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53
54
55
56
57
58
59
60
153.8, 138.8, 136.8, 136.3, 131.2, 130.9, 129.9, 129.2 (2C), 128.3, 128.0, 127.6, 122.7, 122.1, 113.9, 100.0,
45.5, 32.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C29H22 79BrN2O3 525.0808, found 525.0821 ; calcd
for C29H22 81BrN2O3 527.0794, found 527.0806.
Ethyl
4-(3-acetyl-5-(4-bromophenyl)-4-oxo-7-phenyl-4H-pyrano[2,3-b]pyridin-2-
ylamino)benzoate (6cc) was prepared from 4c and ethyl 4-aminobenzoate according to procedure B (2 mL
dioxane, 100 °C, 36 h). The product was precipitated by addition of dioxane (2 mL) and cyclohexane (4
mL), recovered by filtration, and washed with cyclohexane/dioxane 1:1 and petroleum ether. 39 mg (0.067
1
mmol, 67% yield), pale yellow solid. H NMR (400 MHz, CDCl3) δ 13.81 (s, 1H), 8.18 (dm, J = 8.7 Hz,
2H), 8.15 – 8.09 (m, 2H), 7.73 (dm, J = 8.7 Hz, 2H), 7.62 (s, 1H), 7.60 (dm, J = 8.4 Hz, 2H), 7.56 – 7.50 (m,
13
3H), 7.28 (dm, J = 8.4 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). C{1H}
NMR (101 MHz, CDCl3) δ 200.6, 175.5, 166.0, 162.7, 158.7, 157.8, 153.8, 139.7, 138.4, 136.4, 131.3 (2C),
131.1, 129.9, 129.2, 128.0, 127.7, 122.9, 122.32, 122.26, 113.9, 100.6, 61.3, 32.9, 14.5. HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C31H24 79BrN2O5 583.0863, found 583.0854 ; calcd for C31H24 81BrN2O5
585.0848, found 585.0841.
3-Acetyl-5-(4-t-butoxyphenyl)-2-(methylamino)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one (6da)
was prepared from 4d and methylamine (8.03 M solution in absolute ethanol, 14 μL, 0.11 mmol) according
to procedure A (1 mL DCM, rt, 12 h), and was eluted with DCM/EtOAc 9:1. 42 mg (0.095 mmol, 95%
1
yield), white solid (cyclohexane). H NMR (400 MHz, CDCl3) δ 11.46 (br q, J = 4.9 Hz, 1H), 8.14 – 8.07
(m, 2H), 7.61 (s, 1H), 7.54 – 7.45 (m, 3H), 7.31 (dm, J = 8.6 Hz, 2H), 7.05 (dm, J = 8.6 Hz, 2H), 3.30 (d, J
13
= 5.1 Hz, 3H), 2.61 (s, 3H), 1.44 (s, 9H). C{1H} NMR (101 MHz, CDCl3) δ 199.7, 175.4, 165.7, 158.1,
157.9, 156.0, 155.0, 137.1, 134.2, 130.6, 129.2, 129.1, 127.6, 122.9, 122.5, 113.9, 100.2, 78.9, 32.5, 29.1,
28.0. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C27H27N2O4 443.1965, found 443.1960.
Ethyl
4-(3-acetyl-5-(4-t-butoxyphenyl)-4-oxo-7-phenyl-4H-pyrano[2,3-b]pyridin-2-
ylamino)benzoate (6db) was prepared from 4d and ethyl 4-aminobenzoate according to procedure B (2 mL
dioxane, 100 °C, 36 h). The product was precipitated by addition of dioxane (2 mL) and cyclohexane (8
mL), recovered by filtration, and washed with cyclohexane/dioxane 2:1 and petroleum ether. 22 mg (0.038
mmol, 38% yield), white solid. 1H NMR (400 MHz, CDCl3) δ 13.77 (s, 1H), 8.18 (dm, J = 8.7 Hz, 2H), 8.16
– 8.11 (m, 2H), 7.73 (dm, J = 8.7 Hz, 2H), 7.67 (s, 1H), 7.56 – 7.49 (m, 3H), 7.33 (dm, J = 8.6 Hz, 2H), 7.08
(dm, J = 8.6 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.45 (s, 9H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H}
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NMR (101 MHz, CDCl3) δ 200.7, 175.7, 166.0, 162.6, 158.3, 157.9, 156.1, 155.0, 139.8, 136.7, 133.8,
131.2, 130.9, 129.3, 129.1, 127.8, 127.7, 123.0, 122.6, 122.2, 114.0, 100.7, 78.9, 61.3, 32.7, 29.1, 14.5.
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C35H33N2O6 577.2333, found 577.2342.
1
2
3
4
5
6
7
8
9
3-Acetyl-2-(benzylamino)-5-(4-morpholinophenyl)-7-phenyl-4H-pyrano[2,3-b]pyridin-4-one
(6ea) was prepared from 4e and benzylamine (12 μL, 0.11 mmol) according to procedure A (2 mL DCM, rt,
24 h), and was eluted with DCM/EtOAc 9:1. 43 mg (0.081 mmol, 81% yield), bright yellow solid
10
11
12
13
14
15
16
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39
40
41
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44
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46
47
48
49
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52
53
54
55
56
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60
1
(cyclohexane). H NMR (400 MHz, CDCl3) δ 11.87 (t, J = 5.7 Hz, 1H), 8.12 – 8.07 (m, 2H), 7.61 (s, 1H),
7.55 – 7.31 (m, 10H), 6.97 (dm, J = 8.8 Hz, 2H), 4.91 (d, J = 5.8 Hz, 2H), 3.92 – 3.85 (m, 4H), 3.31 – 3.24
(m, 4H), 2.63 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 199.8, 175.7, 164.8, 158.1, 157.8, 154.9, 151.2,
13
137.1, 136.3, 130.6, 130.3, 129.8, 129.14, 129.10, 128.2, 127.9, 127.5, 122.4, 114.4, 113.7, 100.1, 67.0,
48.6, 45.4, 32.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C33H30N3O4 532.2231, found 532.2229.
3-Acetyl-5-(4-morpholinophenyl)-7-phenyl-2-(phenylamino)-4H-pyrano[2,3-b]pyridin-4-one
(6eb) was prepared from 4e and aniline according to procedure B (2 mL dioxane, 85 °C, 12 h). The product
was precipitated by addition of dioxane (2 mL) and cyclohexane (8 mL), recovered by filtration, and washed
1
with cyclohexane/dioxane 2:1 and petroleum ether. 46 mg (0.089 mmol, 89% yield), yellowish solid. H
NMR (400 MHz, CDCl3) δ 13.58 (s, 1H), 8.13 – 8.08 (m, 2H), 7.64 (s, 1H), 7.65 – 7.61 (m, 2H), 7.53 – 7.47
(m, 5H), 7.38 (dm, J = 8.8 Hz, 2H), 7.31 (tm, J = 7.4 Hz, 1H), 6.98 (dm, J = 8.8 Hz, 2H), 3.93 – 3.86 (m,
4H), 3.32 – 3.26 (m, 4H), 2.71 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 200.3, 175.9, 162.7, 158.2,
13
158.1, 154.9, 151.3, 137.0, 135.7, 130.7, 130.1, 129.9, 129.7, 129.1, 127.6, 126.4, 123.2, 122.4, 114.4,
113.9, 100.4, 67.0, 48.7, 32.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C32H28N3O4 518.2074, found
518.2074.
General procedure for the formation of open-ring products 7a-b (Scheme 6). 2-(Methylthio)-8-
azachromone 4a (39 mg, 0.1 mmol) and secondary cyclic amine (0.3 mmol) were dissolved in anhydrous
DCM (1 mL) under argon atmosphere, and the resulting mixture was stirred under the indicated conditions.
After completion, the reaction mixture was diluted with an excess volume of DCM, washed with H2O (3 x)
and brine, then dried over Na2SO4 and concentrated. The product was isolated by flash chromatography on
silica gel and then precipitated by addition of the indicated solvent. Note: safety precautions must be taken
due to the release of toxic methanethiol.
3-(2-(Di(piperidin-1-yl)methylene)-1,3-dioxobutyl)-4,6-diphenyl-2(1H)-pyridone
(7a)
was
prepared from 4a and piperidine according to the general procedure (rt, 36 h), and was isolated by flash
1
chromatography (DCM/MeOH 9:1). 50 mg (0.098 mmol, 98%), yellowish solid (hexane). H NMR (400
MHz, CDCl3) δ 11.76 (br s, 1H), 7.74 – 7.67 (m, 2H), 7.59 – 7.53 (m, 2H), 7.49 – 7.38 (m, 3H), 7.35 – 7.27
(m, 3H), 6.52 (s, 1H), 3.43 (br s, 4H), 3.01 (br s, 4H), 2.02 (s, 3H), 1.78 – 1.28 (m, 12H). C{1H} NMR
13
(151 MHz, CDCl3) δ 190.7, 184.7, 173.9, 163.0, 149.2, 144.6, 139.4, 133.7, 133.2, 129.9, 129.3, 128.6,
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