Synthesis of 2-aryl-4H-pyrano[2,3-b]pyridin-4-ones by a one-pot deprotection-cyclization reaction

Article abstract of DOI:10.1016/j.tet.2009.06.062

An efficient synthesis of 2-aryl-4H-pyrano[2,3-b]pyridine-4-ones is reported, using a one-pot, two step process in the presence of pyridinium hydrochloride. The methodology is compatible with a series of functional groups useful for the synthesis of secon

Full text of DOI:10.1016/j.tet.2009.06.062

Tetrahedron 65 (2009) 6932–6940
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-aryl-4H-pyrano[2,3-b]pyridin-4-ones by a one-pot deprotection–
cyclization reaction
Vladimir Khlebnikov a, Kalpesh Patel a, Xiaojian Zhou a, M. Madhava Reddya, Zhuoyi Su a,
,
Fabrizio S. Chiacchia b, Henrik C. Hansen b
*
a NAEJA Pharmaceuticals Inc., 4290-91A Street, Edmonton, Alberta T6E 5V2, Canada
b Resverlogix Corp., 279 Midpark Way SE, Calgary, Alberta T2X 1M2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2009
Received in revised form 11 June 2009
Accepted 16 June 2009
Available online 21 June 2009
An efficient synthesis of 2-aryl-4H-pyrano[2,3-b]pyridine-4-ones is reported, using a one-pot, two step
process in the presence of pyridinium hydrochloride. The methodology is compatible with a series of
functional groups useful for the synthesis of second generation analogs, as part of our SAR program. In
addition, the method proved to be scalable (>100 g), allowing for efficient synthesis of material to
support animal studies.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
number of O-methyl protected acetophenones and nicotinic acids
are available, we focused heavily on identifying the method that
Naturally occurring polyphenols, such as flavonoids, exhibit
many biological and pharmacological properties, including anti-
cancer, antioxidative, and antiinflammatory activity.1 In addition,
dietary flavonoids, e.g., baicalein2 (Fig. 1) have been reported to
serve a protective role against cardiovascular disease.3,4 Convenient
access to a wide selection of flavonoid analogues would increase
the understanding of flavonoid’s pharmacological potential and be
essential to overcome the poor drug-like properties of natural fla-
vonoids. This could also accelerate the advancement of more fla-
vonoid inspired compounds into drug development.
would allow us to deprotect methoxy protected phenols, as well as
facilitate cyclization tothe final product in one step. However, lack of
general reactions conditions for this transformation prompted us to
explore new methodology. Herein, we describe an efficient syn-
thesis of flavonoid analogs containing one or more nitrogen atom in
the A- and/or B-rings (Fig.1). The method proved especially efficient
for the synthesis of 2-aryl-4H-pyrano-[2,3-b]pyridin-4-ones,
a group of compounds of high interest to us.
2. Results and discussion
3'
4'
2'
B
2.1. Synthesis of 2-(4-hydroxyphenyl)-4H-pyrano[2,3-
b]pyridin-4-one
1
O
C
8
2
5'
HO
HO
O
O
7
6
6'
A
3
Early in the program, we found that the synthesis of 2-aryl-4H-
pyrano-[2,3-b]pyridin-4-ones proceeded with low yields when
following conventional methods for cyclization5 and deprotection
of methoxy protected phenols.8 Especially 2-(4-hydroxyphenyl)-
4H-pyrano[2,3-b]pyridin-4-one (4; Scheme 1), a compound of in-
terest for our discovery program, gave very low yield, limiting our
capability for scaling-up the synthesis to support animal studies.
For example, following the standard conditions by exposing cor-
responding dibenzoylmethane (3) to HBr at 110 ꢀC in order to
achieve the cyclization and deprotection in one step, we were able
to isolate 4 in only 1.5% yield. Variation of the reactions conditions,
including temperature, time, and acid used for the cyclization–
deprotection did not lead to any significant improvements in the
overall yield of compound 4. This prompted us to explore alterna-
tive methodology that would enable the preparation of the
4
5
O
OH
Figure 1. Flavonoid nomenclature and baicalein (right).
Over the years, the synthesis of naturally occurring flavonoids
and their synthetic analoges has received widespread attention.
Although a number of syntheses for flavonoids exist,5 the cyclization
of substituted dibenzoylmethanes derived from the corresponding
esters and ketones is often favored.6,7 Access to methodology based
on readily available building blocks is often essential to maintain
a high throughput in a medicinal chemistry program. Since a large
* Corresponding author. Tel.: þ1 403 254 9252; fax: þ1 403 256 8495.
E-mail address: henrik@resverlogix.com (H.C. Hansen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.062

V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
6933
Table 1
appropriate analogs in
a few steps from readily available
Examples of pyridine$HCl mediated reactions.9 [P]¼pyrrolidino; [M]¼morpholino
substituted 2-alkoxynicotinates and substituted acetophenones.
3
N
OMe
6
4
2
N
O
O
OMe
Pyridine HCl
*
N
OMe
OMe
a
R2'
5
5
Heat
4
6
R2
R1
R1'
O
O
2
B
O
1
O
A
OH
0
0
N
OMe
OMe
b
N
O
Entry A/B
R1
R2
R1
R2
Yield
(%)
1
2
3
4
5
6
7
8
9
10
3/4
H
H
H
H
H
H
H
H
H
H
4-OMe
H
H
H
H
H
H
H
H
H
H
4-OH
3-F, 4-OH
73
59
33
40
69
9
43
52
40
A1/B1
A2/B2
A3/B3
A4/B4
A5/B5
A6/B6
A7/B7
A8/B8
A9/B9
3-F, 4-OMe
3-Cl, 4-OMe
3-Br, 4-OMe
3-Me, 4-OMe
3-OMe, 4-OBn
4-NO2
O
O
O
4
3-Cl, 4-OH
3-Br, 4-OH
3-Me, 4-OH
3-OMe, 4-OH
4-NO2
4-CN
4-NH2
3,5-DiMe, 4-OH 40
3
Scheme 1. Synthesis of compound 4. Yields and conditions: (a) NaH, DMF, rt, 1 h, 92%;
(b) pyridinium hydrochloride, 190 ꢀC, 4 h, 73%.
Interestingly, we found that in the presence of pyridinium
hydrochloride, compound 3 underwent both deprotection of the
two methoxy groups and cyclization to the desired product (4) in
73% yield. Exploring the conditions for the cyclization and
deprotection reaction, we found that the optimal conditions to be
10 equiv of pyridinium hydrochloride at 190 ꢀC for 1–4 h. Typi-
cally, crude 3 was used, simplifying the synthesis. The reactions
were followed by TLC and stopped once the starting material was
consumed.
4-CN
4-NHCOOtBu
3,5-DiMe, 4-
OTBS
4-OMe
4-OMe
H
4-F
4-OiPr
11
12
13
14
15
16
A10/B10 5-Me
A11/B11 6-Me
A12/B12 5-CH2[P]
A13/B13 5-CH2[P]
A14/B14 5-CH2[P]
5-Me
6-Me
5-CH2[P]
5-CH2[P]
5-CH2[P]
4-OH
4-OH
H
4-F
4-OiPr
86
46
42
51
83
A15/B15 5-CH2NMe2 3,5-diMe, 4-
5-CH2NMe2 3,5-diMe, 4-OH 62
OBn
17
A16/B16 5-CH2[P]
3,5-DiMe, 4- 5-CH2[P] 3,5-DiMe, 4-OH 59
OBn
4-OMe
4-F
2.2. Large scale synthesis of 2-(4-hydroxyphenyl)-4H-
pyrano[2,3-b]pyridin-4-one
18
19
20
A17/B17 5-CH2[M]
A18/B18 5-CH2[M]
A19/B19 5-CH2[M]
5-CH2[M]
5-CH2[M]
5-CH2[M]
4-OMe
4-F
4-OH
83
66
57
4-OBn
In addition to being an efficient small scale one pot synthesis,
we also found the method to be scalable. In particular, compound 4,
required for in vivo animal studies, was synthesized in multi-gram
quantities (>100 g) following this methodology. The process only
required small modifications to accommodate synthesis on a larger
scale (>20 g). For large scale synthesis, the final product was iso-
lated by addition of water to the cooled reaction mixture, whereby
the target compound crystallized from the mixture and was iso-
lated by filtration. In addition, we also found that the neutralization
step during the work-up could be eliminated.
cyclization–deprotection was the preferred way to these analogs.
Use of e.g., benzylic acetates as precurcors for the amines led to
displacement of the acetate by the nucleophilic pyridine moiety
and the corresponding pyridinium salt was isolated (Fig. 2).
Cl
N
O
2.3. Scope and limitations
HO
O
Encouraged by the outcome of the initial experiments for the
synthesis of 2-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one,
we decided to explore the generality of this one-pot method.9
We found that the methodology10 was appropriate for a wide
selection of analogs and functional groups (Table 1). The reaction
typically gave 40–80% yields of the isolated product. As observed
for the synthesis of compound 4, the crude dibenzoylmethanes
could be used, reducing the need for additional purification steps.
Methyl, benzyl, and tert-butyldimethylsilyl phenolic ethers were
predictably converted to the corresponding phenols. By reducing
the reaction time (20–40 min) we were able to isolate cyclized
products with the O-methyl ethers intact (Entries 6 and 18), but
reaction conditions had to be adjusted on a case by case basis, and
the reactions needed to be carefully monitored, e.g., by TLC. Iso-
propyl ethers, on the other hand, were stable under the general
reaction conditions (Entry 15). Both nitro (Entry 7) and nitrile
(Entry 8) substituents were tolerated, offering a probe for further
diversification via amide bond formation.11 Analogs containing
benzylic amines either in the 6-position of the A-ring or the 40-
position of the B-ring were of special interest to us. In all cases
(Entries 13/20), we found that the benzylic amines (dimethyl-
amino, pyrrolidino, and morpholino) were stable under the re-
action conditions and the target products were isolated in good to
excellent yields. Installing the benzylic amine prior to the
Figure 2. Example of displacement of benzylic acetates by pyridine under the standard
reaction conditions.
The method also proved to be useful for the synthesis of com-
pounds with nitrogens in other positions of the A-ring (Scheme 2).
OH
X4 OMe
OMe
a
X3
X
X4
O
O
X3
X
2 X1
2 X1
O
O
11: X1=N; X2,3,4 = CH
12: X3=N; X1,2,4 = CH
13: X2,4 = N; X1,3 = CH
B20: X1=N; X2,3,4 = CH
B21: X3=N; X1,2,4 = CH
B22: X2,4 = N; X1,3 = CH
Scheme 2. Deprotection–cyclization with nitrogen in other positions. Yields and
conditions: (a) pyridinium hydrochloride, 190 ꢀC, 1–4 h. B20 (50%), B21 (86%), B22
(13%).
Compounds B20–B22 containing 1 or 2 nitrogens in the A-ring
were successfully synthesized, following the general methodology,
from their dibenzoylmethane precursors 11-13, respectively. The
yields were comparable to the yields for the 2-aryl-4H-pyrano-[2,3-
b]pyridin-4-ones.

6934
V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
3. Conclusions
4.3.2. 2-(4-Hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one (4)
A mixture of the diketone 3 (2 g, 7 mmol) and pyridinium hy-
drochloride (20 g, 0.17 mol) was heated in a round bottom flask at
190 ꢀC for 4 h. The reaction mixture was cooled to room tempera-
ture and diluted with water and neutralized with NaHCO3. The
solution was extracted with ethyl acetate. The organic layer was
washed with water, brine, dried (Na2SO4), and concentrated. The
crude product was purified by column chromatography on silica gel
using 4% methanol in CH2Cl2 to give the title compound 4 as
a colorless crystalline solid (1.23 g, 73%); mp 272–274 ꢀC. 1H NMR
In summary, we have developed an efficient one-pot synthesis
of 2-aryl-4H-pyrano[2,3-b]pyridin-4-ones that facilitates depro-
tection and cyclization in one step. The methodology proved to
tolerate a number of essential functional groups, allowing the
synthesis of a broad set of compounds as part of our medicinal
chemistry program. In addition, we found the method to be scal-
able, permitting support of in vivo animal studies.
4. Experimental
4.1. General
(400 MHz, DMSO-d6)
d
10.38 (s, 1H), 8.77 (dd, J¼4.69, 1.95 Hz, 1H),
8.49 (dd, J¼7.82, 1.95 Hz, 1H), 7.97 (d, J¼8.99 Hz, 2H), 7.62 (dd,
J¼7.62, 4.49 Hz, 1H), 7.01–6.93 (m, 3H); 13C NMR (100 MHz, DMSO-
d6) d 178.2, 164.2, 161.9, 160.8, 153.9, 136.3, 129.2, 123.2, 121.9, 118.7,
Solvents and reagents were used as purchased from commercial
suppliers, unless otherwise noted. Dry THF was obtained via distil-
lation over sodium using benzophenone as an indicator. Anhydrous
THF was purchased from Sigma–Aldrich. Yields refer to chromato-
graphically and spectroscopically (1H NMR) homogeneous materials,
unlessotherwisestated. Reported meltingpointsare of materialsthat
have been purified by column chromatography. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
Macherey-Nagel (MN) Alugram SIL G/UV254 silica gel 60 with fluo-
rescent indicator UV254 plates (catalogue #818 133) Sigma–Aldrich
silica gel plates (catalogue #Z193291-1PAK) using phosphomolybdic
acid in absolute EtOH and heat as a developing agent. NMR spectra
were recorded on Varian NMR AS400 instrument using residual
undeuterated solvent as an internal reference. Low resolution mass
spectra (MS) were recorded on a Waters micromass ZQ using elec-
trospray ionization-ion trap (ESI). The following compounds were
commercially available and used as supplied: acetophenone,
40-methoxyacetophenone, 40-fluoroacetophenone, 40-aminoacetop-
henone, 4-acetylbenzonitrile, 40-nitroacetophenone, 30-fluoro-40-
methoxyacetophenone, 30-chloro-40-methoxyacetophenone, 30-bro-
mo-40-methoxyacetophenone, 40-isopropoxyacetophenone, 40-ben-
zyloxyacetophenone, and 40-hydroxy-3,5-dimethylacetophenone.
116.7, 105.8; MS (ESþ) m/z: 240.07. Anal. Calcd for C14H9NO4
(239.23): C, 70.29; H, 3.79; N, 5.85. Found: C, 70.22; H, 3.73; N, 5.73.
4.3.3. 1-(3-Fluoro-4-methoxyphenyl)-3-(2-methoxypyridin-3-
yl)propane-1,3-dione (A1)
A 50 mL flask was charged with methyl 2-methoxynicotinate
(1)12 (2.50 g, 15 mmol), dry DMF (10 mL) and sodium hydride
(0.745 g, 19 mmol, 60% in mineral oil). To the mixture was added 30-
fluoro-40-methoxyacetophenone (2.60 g, 15.5 mmol) in anhydrous
DMF (6 mL) over 5–10 min. The reaction mixture was stirred for
30 min. The mixture was poured into an NH4Cl solution (50 mL).
The yellow solid was filtered off and washed with water and pu-
rified by column chromatography (n-hexane/ethyl acetate 4:1) to
give the title compound A1 (3.0 g, 66%). 1H NMR (400 MHz, CDCl3)
d
8.35–8.28 (m, 2H), 7.82–7.77 (m, 1H), 7.76–7.70 (m, 1H), 7.20 (s,
1H), 7.05 (td, J¼7.24, 2.19 Hz, 2H), 4.13 (s, 3H), 3.98 (s, 3H).
4.3.4. 2-(3-Fluoro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-
one (B1)
The title compound was synthesized following general pro-
cedure A from A1 (0.8 g, 2.6 mmol). The title compound was iso-
lated as yellow crystalline solid (0.4 g, 59%); mp 267–268 ꢀC. 1H
NMR (400 MHz, DMSO-d6)
J¼7.33 Hz, 1H), 7.86–7.70 (m, 2H), 7.62–7.49 (m, 1H), 7.00–6.81 (m,
2H); 13C NMR (101 MHz, DMSO-d6)
178.2,162.9,160.7,154.0,153.1,
150.7, 150.2, 150.0, 136.4, 124.4,123.4, 122.1,122.0,118.9,118.7,115.2,
d 10.25 (br s, 1H), 8.71 (br s, 1H), 8.43 (d,
4.2. The cyclization reaction (A/B)
d
A mixture of dibenzoylmethane A and pyridinium hydrochlo-
ride (10 equiv) was heated to 190 ꢀC for 1–4 h. The reaction was
followed by TLC, and the reaction mixture was cooled to room
temperature once the starting material was consumed. Water was
added, and the mixture was neutralized with NaHCO3. The product
was extracted with ethyl acetate. The organic layer was washed
with water, brine, dried over Na2SO4 and concentrated to dryness.
The crude product was purified by chromatography to give the
desired cyclized product B.
115.0, 106.5; 19F NMR (376 MHz, DMSO-d6)
d
ꢁ135.5 (t, 1F); MS
(ESþ) m/z: 257.85. Anal. Calcd for C14H8FNO3 (257.22): C, 65.37; H,
3.13; N, 5.45. Found: C, 65.51; H, 3.22; N, 5.42.
4.3.5. 1-(3-Chloro-4-methoxyphenyl)-3-(2-methoxypyridin-3-
yl)propane-1,3-dione (A2)
To sodium hydride (0.48 g, 12 mmol, 60% in mineral oil) in an-
hydrous DMF (10 mL) was added a solution of 30-chloro-40-
methoxyacetophenone (1.85 g, 10 mmol) in anhydrous DMF (5 mL)
at 0 ꢀC under nitrogen. The reaction mixture was stirred at 0 ꢀC for
5 min, then at room temperature for 30 min. The reaction mixture
was cooled to 0 ꢀC. A solution of ethyl 2-methoxynicotinate13
(1.81 g, 10 mmol) in anhydrous DMF (5 mL) was added slowly. The
reaction mixture was stirring at room temperature under nitrogen
for 20 h. Water (20 mL) was added and the mixture was extracted
with ethyl acetate (2ꢂ100 mL). The combined organic layers were
washed with brine and dried (Na2SO4), and concentrated to give
a dark colored solid. The solid was triturated with ether to give the
title compound A2 as a yellow amorphous solid (1.64 g, 51% crude).
The crude product was used without further purification. MS (ESþ)
m/z: 319.96 (100%, M) and 321.96 (35%, Mþ2).
4.3. Synthetic details
4.3.1. 1-(4-Methoxyphenyl)-3-(2-methoxypyridin-3-yl)propane-
1,3-dione (3)
To a dry 250 mL round bottom flask was added sodium hydride
(5.00 g,126 mmol, 60% in mineral oil) and methyl 2-methoxynicotinate
(1)12 (10.5 g, 62.8 mmol) dissolved in dry DMF (50 mL). A solution of 40-
methoxyacetophenone (2) (9.9 g, 66 mmol) in dry DMF (20 mL) was
added dropwise over 30 min. The mixture was stirred for 1 h at room
temperature. An aqueous solution of NaH2PO4 (25.0 g in 400 mL water)
was added carefully to adjust the pH to 7. The precipitated solid was
filtered off, washed with cold water and dried under vacuum to give
crude 1-(4-methoxyphenyl)-3-(2-methoxypyridin-3-yl)propane-1,3-
dione (3) as a yellow solid (16.4 g, 92%). The crude material was used
4.3.6. 2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-
one (B2)
without further purification. 1H NMR (400 MHz, CDCl3)
d 8.32 (dd,
J¼7.41, 1.95 Hz, 1H), 8.28 (dd, J¼4.68, 1.95 Hz, 1H), 7.98 (m, 2H), 7.25 (s,
The title compound was synthesized following general pro-
cedure A from A2 (1.36 g, 4.21 mmol). The title compound was
1H), 7.04 (dd, J¼7.61, 4.88 Hz,1H), 7.00 (m, 2H), 4.12 (s, 3H), 3.89 (s, 3H).

V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
6935
isolated as a yellow crystalline solid (0.39 g, 33%); mp 259–262 ꢀC.
1H NMR (400 MHz, DMSO-d6)
J¼7.33 Hz, 1H), 7.80 (br s, 1H), 7.74 (d, J¼7.91 Hz, 1H), 7.62–7.50 (m,
1H), 6.93 (d, J¼8.20 Hz, 1H), 6.87 (s, 1H), 2.18 (s, 3H); 13C NMR
d
11.20 (s, 1H), 8.78 (dd, J¼4.49,
2.15 Hz, 1H), 8.49 (dd, J¼7.82, 1.95 Hz, 1H), 8.10 (d, J¼2.34 Hz, 1H),
7.94 (dd, J¼8.60, 2.34 Hz, 1H), 7.63 (dd, J¼7.62, 4.49 Hz, 1H), 7.16 (d,
(101 MHz, DMSO-d6) d 178.1, 164.3, 160.8, 160.1, 153.8, 136.3, 129.7,
126.6, 125.7, 123.2, 121.6, 118.7, 115.8, 105.6, 16.6; MS (ESþ) m/z:
253.98. Anal. Calcd for C15H11NO3 (253.22): C, 71.14; H, 4.38; N,
5.53. Found: C, 70.82; H, 4.38; N, 5.68.
J¼8.60 Hz, 1H), 7.06 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 178.3,
162.7,160.8,157.3, 154.1,136.4, 128.9, 127.6,123.4,123.2, 121.4, 118.8,
117.7, 106.7; MS (ESþ) m/z: 275.94þ273.92 (two isotopes). Anal.
Calcd for C14H8ClNO3 (273.68): C, 61.44; H, 2.95; N, 5.12. Found: C,
61.52; H, 3.03; N, 5.13.
4.3.11. 1-(4-(Benzyloxy)-3-methoxyphenyl)-3-(2-methoxypyridin-
3-yl)propane-1,3-dione (A5)
A 100 mL dry flask was charged with methyl 2-methoxy-
4.3.7. 1-(3-Bromo-4-methoxyphenyl)-3-(2-methoxypyridin-3-
yl)propane-1,3-dione (A3)
nicotinitate12
(2.2 g,
13 mmol),
40-benzyloxy-30-methoxy-
acetophenone15 (3.4 g, 13 mmol) and anhydrous DMF (10 mL).
Sodium hydride (0.52 g, 13 mmol, 60% in mineral oil) was added
and the reaction mixture was stirred for 2 h at room temperature.
The reaction mixture was poured into water and extracted with
ethyl acetate (150 mL). The organic layer was washed with water
(2ꢂ100 mL), brine (100 mL), dried (Na2SO4), and concentrated to
give the title compound (5.0 g, 98%). The crude product was used
To sodium hydride (0.206 g, 5.16 mmol, 60% in mineral oil) and
anhydrous DMF (5 mL) was added a solution of 30-bromo-40-
methoxyacetophenone (0.99 g, 4.3 mmol) in anhydrous DMF
(3 mL) at 0 ꢀC under nitrogen. The reaction mixture was stirred at
0 ꢀC for 5 min, then at room temperature for 30 min. The mixture
was cooled to 0 ꢀC and a solution of ethyl 2-methoxynicotinate13
(1.8 g, 10 mmol) in anhydrous DMF (3 mL) was added slowly. The
reaction mixture was stirred at room temperature under nitrogen
for 20 h. Water (20 mL) was added and the mixture was extracted
with ethyl acetate (2ꢂ100 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to give a dark
colored solid. The solid was triturated with ether to give the title
compound (1.3 g, 84%) as an amorphous yellow solid. The crude
product was used without further purification. 1H NMR (400 MHz,
without further purification. 1H NMR (400 MHz, CDCl3)
d 8.33 (dd,
J¼7.62, 2.05 Hz, 1H), 7.64–7.59 (m, 1H), 7.64–7.32 (m, 9H), 6.95 (dd,
J¼8.35, 1.90 Hz, 1H), 5.26 (s, 2H), 4.11 (d, J¼2.34 Hz, 3H), 3.99 (d,
J¼2.05 Hz, 3H).
4.3.12. 2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridin-
4-one (B5)
Compound A5 (4.0 g, 10 mmol) and pyridine hydrochloride
(12.0 g, 10 mmol) were mixed and heated to 170–190 ꢀC for 20 min.
The reaction mixture was cooled and poured into water (100 mL).
The mixture was extracted with ethyl acetate (3ꢂ200 mL). The
combined organic layers were washed with brine (3ꢂ100 mL), dried
(Na2SO4), and concentrated. The solid was further purified by
refluxing in methanol (40 mL). The solution was cooled and filtered
to give the title compound (250 mg, 9%) as a crystalline solid; mp
CDCl3)
d
8.35–8.28 (m, 2H), 8.20 (d, J¼2.34 Hz, 1H), 7.95 (dd, J¼8.60,
2.34 Hz, 1H), 7.22 (s, 1H), 7.08–6.96 (m, 2H), 4.13 (s, 3H), 3.98 (s,
3H); MS (ESþ) m/z: 363.91 (M) and 365.91 (two isotopes).
4.3.8. 2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-
one (B3)
The title compound was synthesized following general pro-
cedure A from A3 (1.31 g, 3.6 mmol). The title compound was iso-
lated as a crystalline yellow solid (0.45 g, 40%); mp 267–272 ꢀC. 1H
253–255 ꢀC.1H NMR (400 MHz, DMSO-d6)
d 10.02 (br s,1H), 8.77 (br
s, 1H), 8.48 (br s, 1H), 7.61 (d, J¼8.77 Hz, 3H), 7.08 (br s, 1H), 6.98 (d,
NMR (400 MHz, DMSO-d6)
d
11.25 (s, 1H), 8.78 (dd, J¼4.69, 1.95 Hz,
J¼7.60 Hz,1H), 3.92 (br s, 3H); 13C NMR (101 MHz, DMSO-d6)
d 178.2,
1H), 8.49 (dd, J¼7.62, 2.15 Hz, 1H), 8.24 (d, J¼2.34 Hz, 1H), 7.98 (dd,
164.0, 160.8, 153.9, 151.5, 148.7, 136.3, 123.3, 122.2, 121.1, 118.7, 116.5,
110.7, 106.1, 56.6; MS (ESþ) m/z: 269.91. Anal. Calcd for C15H11NO4
(269.26): C, 66.91; H, 4.12; N, 5.20. Found: C, 67.29; H, 4.11; N, 5.38.
J¼8.79, 2.15 Hz, 1H), 7.63 (dd, J¼7.62, 4.49 Hz, 1H), 7.13 (d,
J¼8.99 Hz, 1H), 7.06 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 178.2,
162.6, 160.7, 158.3, 154.1, 136.4, 131.8, 128.2, 123.6, 123.4, 118.8, 117.7,
110.9, 106.7; MS (ESþ) m/z: 317.84, 239.9. Anal. Calcd for
C14H8BrNO3 (318.12): C, 52.86; H, 2.53; N, 4.40. Found: C, 53.61; H,
2.74; N, 4.72.
4.3.13. 1-(2-Methoxypyridin-3-yl)-3-(4-nitrophenyl)propane-1,3-
dione (A6)
To a stirred solutionof 2-methoxynicotinic acid13 (2.3 g,15 mmol)
in anhydrous THF (75 mL) was added N-methylmorpholine (1.5 g,
15 mmol). The reaction mixture was cooled to ꢁ10 ꢀC and ethyl
chloroformate (1.6 g, 15 mmol) was added dropwise. The reaction
mixture was stirred at ꢁ10 ꢀC for 15 min. and then at room temper-
ature for 10 h. Water (50 mL) was added, and the solution was
extracted with ethyl acetate. The organic layer was dried (Na2SO4),
andconcentratedtogive theacidchlorideasa colorless liquid(3.29 g,
97%). To a solution of acid chloride (3.28 g, 14.6 mmol) and 40-nitro-
acetophenone (2.5 g,15 mmol) in anhydrous THF (75 mL) was added
lithium bis(trimethylsilyl) amide (18 mL, 1.0 M solution in THF) at
ꢁ30 ꢀC over a period of 45 min. The reaction mixture was stirred at
ꢁ30 ꢀC for 30 min. The reaction mixture was stirred for another 15 h
at room temperature. The reaction mixture was diluted with ethyl
acetate (200 mL), and saturated NH4Cl solution (50 mL) was added.
The organic layer was dried (Na2SO4), and concentrated to give the
crude product which was triturated with ether to give the title
compound(2.79 g, 62%). The crudeproductwasused without further
4.3.9. 1-(4-Methoxy-3-methylphenyl)-3-(2-methoxypyridin-3-
yl)propane-1,3-dione (A4)
A 100 mL dry flask was charged with methyl 2-methoxy-
nicotinate12 (2.5 g, 15 mmol), anhydrous DMF (10 mL) and sodium
hydride (0.9 g, 23 mmol, 60% in mineral oil). To the reaction mix-
ture was added 40-methoxy-30-methylacetophenone14 (2.58 g,
15.7 mmol) in anhydrous DMF (3 mL) and the reaction mixture was
stirred for 2 h. The mixture was poured into water (120 mL) and
acetic acid (3 mL). The yellow solid was isolated by filtration and
washed with water and dried. The crude compound was purified by
column chromatography (n-hexane/ethyl acetate 3:1) to give the
title compound (3.4 g, 76%). 1H NMR (400 MHz, CDCl3)
d 8.34–8.26
(m, 2H), 7.86 (dd, J¼8.50, 1.76 Hz, 1H), 7.81 (s, 1H), 7.24 (s, 1H), 7.04
(dd, J¼7.62, 5.57 Hz,1H), 6.90 (d, J¼8.50 Hz,1H), 4.12 (s, 3H), 3.91 (s,
3H), 2.28 (s, 3H).
4.3.10. 2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridin-
4-one (B4)
The title compound was synthesized following general pro-
cedure A from A4 (1.0 g, 3.3 mmol). The title compound was iso-
lated as a grey crystalline solid (0.58 g, 69%); mp 300–302 ꢀC. 1H
purification. 1H NMR (400 MHz, DMSO-d6)
d 8.47–8.20 (m, 6H), 7.41
(s, 1H), 7.23 (dd, J¼7.42, 5.08 Hz, 1H), 4.07 (s, 3H).
4.3.14. 2-(4-Nitrophenyl)-4H-pyrano[2,3-b]pyridin-4-one (B6)
The title compound was synthesized following general pro-
cedure A from A6 (2.16 g, 7.19 mmol). The title compound was
NMR (400 MHz, DMSO-d6) d 10.25 (br s, 1H), 8.71 (br s, 1H), 8.43 (d,

6936
V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
isolated as a brown crystalline solid (0.82 g, 43%); mp 261–263 ꢀC.
1H NMR (400 MHz, DMSO-d6)
8.84 (dd, J¼4.49, 2.15 Hz, 1H), 8.54
(dd, J¼7.82, 1.95 Hz, 1H), 8.44–8.36 (m, 4H), 7.68 (dd, J¼7.82,
4.69 Hz, 1H), 7.35 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
178.6,
isolated as a yellow crystalline solid (0.25 g, 40%); mp 254–
255 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
d
8.76 (d, J¼4.69 Hz, 1H),
8.48 (d, J¼7.82 Hz, 1H), 7.90 (d, J¼8.58 Hz, 2H), 7.61 (dd, J¼7.42,
d
4.69 Hz, 1H), 7.12–6.78 (m, 6H); 13C NMR (100 MHz, DMSO-d6)
161.3, 160.8, 154.6, 149.9, 137.5, 136.6, 128.6, 124.9, 123.8, 118.9,
110.4; MS (ESþ) m/z: 268.88 (M). Anal. Calcd for
C14H8N2O4$0.25H2O (272.72): C, 61.65; H, 3.14; N, 10.27. Found: C,
61.77; H, 3.31; N, 10.26.
d 177.9, 164.3, 160.8, 153.7, 136.2, 128.8, 123.2, 118.8, 116.8, 104.8;
MS (ESþ) m/z: 238.89 (Mþ1). Anal. Calcd for C14H10N2O2$HCl
(274.70): C, 61.21; H, 4.04; N, 10.20. Found: C, 61.23; H, 3.91; N,
9.98.
4.3.15. 4-(3-(2-Methoxypyridin-3-yl)-3-oxopropanoyl)-
4.3.19. 1-(4-(tert-Butyldimethylsilyloxy)-3,5-dimethylphenyl)-3-(2-
benzonitrile (A7)
methoxypyridin-3-yl)propane-1,3-dione (A9)
A dry 50 mL flask was charged with methyl 2-methoxy-
nicotinitate12 (2.50 g, 14.9 mmol), 4-acetylbenzonitrile (2.25 g,
15.9 mmol) and anhydrous DMF (10 mL). Sodium hydride (0.745 g,
18.6 mmol, 60% in mineral oil) was added and the reaction mixture
was stirred for 30 min, then poured into water (100 mL) and acetic
acid (2 mL). The yellow solid was washed with water and dissolved
into dichloromethane. The organic solution was washed with brine,
dried (Na2SO4), and concentrated. The residue was purified by
column chromatography (n-hexane/ethyl acetate 3:1) to give the
To
a
solution of 30,50-dimethyl-40-hydroxyacetophenone
(2.5 g, 15 mmol) in anhydrous DMF (75 mL) was added imidazole
(3.3 g, 48 mmol) and tert-butyldimethylsilylchloride (2.7 g,
18 mmol). The reaction mixture was stirred at room temperature
under nitrogen for 15 h. Water (200 mL) was added, and the
mixture was extracted with ethyl acetate (200 mL). The organic
layer was washed with water (2ꢂ100 mL), brine (100 mL), dried
(Na2SO4), and concentrated to give 1-(4-(tert-butyldimethylsily-
loxy)-3,5-dimethylphenyl)ethanone (6) as a colorless oil (4.4 g,
quantitative yield). The crude product was used without further
title compound (1.7 g, 41%). 1H NMR (400 MHz, CDCl3)
d 8.33 (m,
2H), 8.06 (d, J¼8.19 Hz, 2H), 7.79 (d, J¼8.19 Hz, 2H), 7.32 (s, 1H),
purification. 1H NMR (400 MHz, CDCl3)
d 7.40 (s, 2H), 2.32 (s,
7.13–7.02 (m, 1H), 4.13 (s, 3H).
3H), 2.04 (s, 6H), 0.82 (s, 9H), 0.00 (s, 6H). To a stirred solution of
compound 6 (1.6 g, 5.6 mmol) in anhydrous THF (15 mL) was
added lithium bis(trimethylsilyl) amide (6.8 mL, 1.0 M solution in
THF) at ꢁ40 ꢀC over a period of 15 min under nitrogen. The
mixture was stirred at ꢁ40 ꢀC for 15 min. A solution of ethyl 2-
methoxynicotinate13 in anhydrous THF (15 mL) was added
slowly. The stirring was continued at ꢁ40 ꢀC for 10 min. The
mixture was allowed to warm to room temperature and stirred
for another 15 h. The reaction mixture was diluted with ethyl
4.3.16. 4-(4-Oxo-4H-pyrano[2,3-b]pyridin-2-yl)benzonitrile (B7)
The title compound was synthesized following general pro-
cedure A from A7 (0.7 g, 2.5 mmol). The title compound was
isolated as a light yellow crystalline solid (0.32 g, 52%); mp 250–
252 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
8.81 (dd, J¼4.69, 2.05 Hz,
1H), 8.51 (dd, J¼7.62, 2.05 Hz, 1H), 8.29–8.24 (m, 2H), 8.08–8.03 (m,
2H), 7.65 (dd, J¼7.77, 4.54 Hz, 1H), 7.28 (s, 1H); 13C NMR (101 MHz,
DMSO-d6)
d
178.6,161.7,160.8,154.6,136.6,135.8,133.8,127.9,123.7,
acetate (200 mL) and a saturated aqueous NH4Cl solution
118.9, 118.9, 114.7, 110.0; MS (ESþ) m/z: 248.90. Anal. Calcd for
C15H8N2O2 (248.27): C, 72.58; H, 3.25; N, 11.27. Found: C, 72.62; H,
3.08; N, 11.31.
(50 mL) was added. The organic layer was isolated, dried
(Na2SO4), and concentrated to give the desired crude compound
(2.4 g). The compound was used in the next step without further
purification. 1H NMR (400 MHz, CDCl3)
d 8.35–8.25 (m, 1H), 8.15
4.3.17. tert-Butyl 4-[3-(2-methoxypyridin-3-yl)-3-
oxopropanoyl]phenylcarbamate (A8)
(d, J¼7.42 Hz, 1H), 7.62 (s, 2H), 7.26 (s, 1H), 6.97–6.90 (m, 1H),
4.05 (s, 3H), 1.03 (s, 9H), 0.22 (s, 6H).
Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was added to a solu-
tion of 40-aminoacetophenone (2.7 g, 20 mmol) in dioxane (50 mL).
The reaction mixture was stirred at 60 ꢀC for 15 h. The solvent was
removed and the residue was dissolved in ethyl acetate and washed
with water (2ꢂ50 mL), brine (50 mL), dried (Na2SO4), and con-
centrated to give the crude product, which was purified by column
chromatography (15% ethyl acetate in n-hexanes) to give tert-butyl
4-acetylphenylcarbamate16 (5) as a white solid (2.7 g, 58%). 1H NMR
4.3.20. 2-(4-Hydroxy-3,5-dimethylphenyl)-4H-pyrano[2,3-
b]pyridin-4-one (B9)
The title compound was synthesized following general pro-
cedure A from crude A9 (2.3 g, 5.6 mmol). The title compound was
isolated as an off-white crystalline solid (0.60 g, 40% over two
steps); mp 295–297 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 9.19 (s, 1H),
8.76 (d, J¼4.69 Hz, 1H), 8.48 (d, J¼7.82 Hz, 1H), 7.73 (s, 2H), 7.61 (dd,
(400 MHz, CDCl3)
d
7.92 (d, J¼8.97 Hz, 2H), 7.46 (d, J¼8.58 Hz, 2H),
J¼7.42, 4.69 Hz, 1H), 6.95 (s, 1H), 2.27 (s, 6H); 13C NMR (100 MHz,
6.73 (br s, 1H), 2.57 (s, 3H), 1.53 (s, 9H). To a solution of compound 5
(2.4 g, 10 mmol) in anhydrous THF (50 mL) was added lithium
bis(trimethylsilyl) amide solution (22 mL, 1.0 M in THF) at ꢁ40 ꢀC
over a period of 30 min under nitrogen. The mixture was stirred at
ꢁ40 ꢀC for 15 min. A solution of ethyl 2-methoxynicotinate in an-
hydrous THF (10 mL) was added slowly. The reaction mixture was
stirred at ꢁ40 ꢀC for 10 min, then allowed to warm to room tem-
perature. After 5 h, a saturated aqueous NH4Cl solution (100 mL)
was added. The mixture was extracted with ethyl acetate (300 mL).
The organic layer was isolated and dried (Na2SO4). The crude
compound was purified by column chromatography (15% ethyl
acetate in n-hexanes) to give the title compound as a yellow solid
DMSO-d6) d 178.1, 164.4, 160.8, 158.0, 153.9, 136.3, 127.6, 125.6,
123.3, 121.7, 118.8, 105.8, 17.3; MS (ESþ) m/z: 268.91 (Mþ1), 267.88
(M). Anal. Calcd for C16H13NO3 (267.28): C, 71.90; H, 4.90; N, 5.24.
Found: C, 71.68; H, 4.83; N, 5.29.
4.3.21. 1-(2-Chloro-5-methylpyridin-3-yl)-3-(4-
methoxyphenyl)propane-1,3-dione (A10)
To a mixture of methyl 2-chloro-5-methylnicotinate17 (0.90 g,
4.8 mmol) and NaH (0.38 g, 9.6 mmol, 60% in mineral oil) in an-
hydrous DMF (10 mL) was added 40-methoxyacetophenone (0.76 g,
5.0 mmol). The reaction mixture was stirred for 2 h at room tem-
perature. The reaction mixture was poured into water and extrac-
ted with ethyl acetate (150 mL). The organic layer was washed with
water (2ꢂ100 mL), brine (100 mL), dried (Na2SO4), and concen-
trated to give the crude product. The crude product was purified by
chromatography (n-hexane/ethyl acetate 4:1) to give the title
(2.9 g, 79%). 1H NMR (400 MHz, CDCl3)
d 8.35–8.27 (m, 2H), 7.95 (d,
J¼8.97 Hz, 2H), 7.50 (d, J¼8.58 Hz, 2H), 7.25 (s, 1H), 7.03 (dd, J¼7.42,
4.69 Hz, 1H), 6.80 (br s, 1H), 4.15 (s, 3H), 1.560 (s, 9H).
4.3.18. 2-(4-Aminophenyl)-4H-pyrano[2,3-b]pyridin-4-one (B8)
The title compound was synthesized following general pro-
cedure A from A8 (3.0 g, 26 mmol). The title compound was
compound (0.36 g, 25%). 1H NMR (400 MHz, CDCl3)
d 8.29 (br s, 1H),
7.94 (d, J¼5.55 Hz, 2H), 7.85 (br s, 1H), 6.97 (d, J¼5.26 Hz, 2H), 6.78
(br s, 1H), 3.88 (s, 3H), 2.38 (s, 3H).

V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
6937
4.3.22. 2-(4-Hydroxyphenyl)-6-methyl-4H-pyrano[2,3-b]pyridin-
4-one (B10)
1H), 8.15 (s,1H), 4.04 (s, 3H), 3.90 (s, 3H), 3.58 (s, 2H), 2.50 (br s, 4H),
1.79 (br s, 4H). To a mixture of compound 8 (0.50 g, 2.0 mmol) and
acetophenone (0.24 g, 2.0 mmol) in anhydrous DMF (4 mL) was
added sodium hydride (0.16 g, 60% in mineral oil), and the reaction
mixture was kept overnight at room temperature. The mixture was
poured intowater (80 mL)andextracted with CH2Cl2 (3ꢂ80 mL). The
combined organic layers were washed with water, brine, dried
(Na2SO4), and concentrated to yield the title compound (0.45 g, 67%).
The crude compound was used without further purification.1H NMR
The title compound was synthesized following general pro-
cedure A from crude A10 (0.28 g, 0.92 mmol). The title compound
was isolated as a red crystalline solid (0.20 g, 86%); mp 268–270 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
10.28 (br s, 1H), 8.60 (s, 1H), 8.30 (s,
1H), 7.90 (m, 2H), 6.95 (m, 3H), 2.40(s, 3H); 13C NMR (101 MHz,
DMSO-d6)
d 178.1, 164.4, 162.3, 160.8, 154.5, 136.3, 133.4, 129.2,
122.3, 118.8, 117.5, 105.8, 17.3; MS (ESþ) m/z: 253.95. Anal. Calcd for
C15H11NO3 (253.26): C, 71.14; H, 4.38; N, 5.53. Found: C, 71.59; H,
4.52; N, 5.68.
(400 MHz, DMSO-d6)
d 8.70 (s, 1H), 8.60 (s, 1H), 8.10 (m, 2H), 7.50
(m, 3H), 7.20 (s, 1H), 4.20 (s, 2H), 4.10 (s, 3H), 2.20 (br s, 8H).
4.3.23. 1-(2-Methoxy-6-methylpyridin-3-yl)-3-(4-
methoxyphenyl)propane-1,3-dione (A11)
4.3.26. 2-Phenyl-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-
b]pyridin-4-one (B12)
To a mixture of NaH (637 mg, 26.5 mmol, 60% in mineral oil) in
dry DMF (20 mL) at 0 ꢀC was added 40-methoxyacetophenone
(3.62 g, 24.1 mmol) in dry DMF (10 mL) over 30 min. After 1 h,
methyl 2-methoxy-6-methylnicotinate18 (4.37 g, 24.1 mmol) in dry
DMF (10 mL) was added slowly on cooling. The mixture was stirred
for 16 h at room temperature. The reaction mixture was quenched
by addition of a saturated aqueous NH4Cl solution and diluted with
water. The solid was filtered off, washed with water and dried to
give the title compound (6.18 g, 86%). The crude product was used
The title compound was synthesized following general pro-
cedure A from crude A12 (0.45 g, 1.3 mmol). The hydrochloride of
the title compound was isolated as a grey crystalline solid (0.19 g,
42%); mp 294–296 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 11.00 (br s,
1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.20 (m, 2H), 7.70 (m, 3H), 7.20 (s, 1H),
4.60 (s, 2H), 3.40 (m, 4H), 2.10–1.80 (m, 4H); 13C NMR (100 MHz,
DMSO-d6) d 178.2,163.8, 156.0, 138.9, 132.9, 131.3,129.9, 127.2, 127.1,
118.3, 108.2, 53.6, 53.3, 23.2; MS (ESþ) m/z: 306.94. Anal. Calcd for
C19H18N2O2$HCl (342.83): C, 66.57; H, 5.59; N, 8.17. Found: C,
66.81; H, 5.31; N, 8.18.
without further purification. 1H NMR (400 MHz, CDCl3)
d 8.22 (d,
J¼7.82 Hz, 1H), 7.97 (d, J¼8.99 Hz, 2H), 7.20 (s, 1H), 7.00–6.97 (m,
2H), 6.87 (d, J¼7.82 Hz, 1H), 4.10 (s, 3H), 3.89 (s, 3H), 2.51 (s, 3H).
4.3.27. 1-(4-Fluorophenyl)-3-(2-methoxy-5-(pyrrolidin-1-
ylmethyl)pyridin-3-yl)propan-1,3-dione (A13)
4.3.24. 2-(4-Hydroxyphenyl)-7-methyl-4H-pyrano[2,3-b]pyridin-
4-one (B11)
To a stirred solution of compound 8 (0.50 g, 2.0 mmol) and 40-
fluoroacetophenone (0.28 g, 2.0 mmol) in anhydrous DMF (3 mL)
was added sodium hydride (0.16 g, 2.0 mmol, 60% suspension in
mineral oil) in small portions under nitrogen. The reaction mixture
was stirred overnight at room temperature. A saturated aqueous
solution of NH4Cl was added. The mixture was extracted with ethyl
acetate (100 mL). The organic layer was washed with water
(30 mL), brine (30 mL), dried (Na2SO4), and concentrated to give
a brown solid (0.45 g), which was used in next step without further
The title compound was synthesized following general pro-
cedure A from crude A11 (3.0 g, 10 mmol). The title compound was
isolated as a yellow crystalline solid (1.15 g, 46%); mp 303–305 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
10.36 (s, 1H), 8.35 (d, J¼7.42 Hz,
1H), 7.95 (d, J¼8.21 Hz, 2H), 7.48 (d, J¼7.82 Hz, 1H), 7.02–6.86 (m,
3H), 2.62 (s, 3H); 13C NMR (101 MHz, DMSO-d6)
178.1, 164.1, 163.8,
d
161.8, 160.4, 136.3, 129.1, 123.1, 122.0, 116.7, 116.3, 105.7, 25.0; MS
(ESþ) m/z: 253.88. Anal. Calcd for C15H11NO3 (253.26): C, 71.14; H,
4.38; N, 5.53. Found: C, 71.16; H, 4.37; N, 5.49.
purification. 1H NMR (400 MHz, CDCl3)
7.30 (s, 1H), 7.20 (m, 2H), 4.20 (s, 2H), 4.10 (s, 3H), 2.20 (br s, 8H); 19F
NMR (376 MHz, DMSO-d6)
ꢁ107.8.
d 8.60 (m, 2H), 8.10 (m, 2H),
d
4.3.25. 1-(2-Methoxy-5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-3-
phenylpropane-1,3-dione (A12)
4.3.28. 2-(4-Fluorophenyl)-6-(pyrrolidin-1-ylmethyl)-4H-
pyrano[2,3-b]pyridin-4-one (B13)
To a solution of methyl 2-chloro-5-methylnicotinate17 (14.0 g,
75 mmol) in anhydrous methanol (40 mL) was added sodium
methoxide (31 mL, 140 mmol, 25% in methanol) and the reaction
was heated at reflux overnight. Acetic acid was added to the mix-
ture until neutral. The mixture was concentrated to remove the
methanol. The residue was poured into water and extracted with
CH2Cl2. The organic layer was washed with water, brine, dried
(Na2SO4), and concentrated to give methyl 2-methoxy-5-methyl-
The title compound was synthesized following general pro-
cedure A from crude A13 (0.45 g, 1.3 mmol). The hydrochloride of
the title compound was isolated as a yellow crystalline solid (0.21 g,
51%); mp 265–268 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 11.10 (br s,
1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.20 (m, 2H), 7.50 (m, 2H), 7.20 (s, 1H),
4.50 (s, 2H), 3.3 (m, 2H), 3.0 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H); 13C
NMR (100 MHz, DMSO-d6)
d 178.2, 162.8, 160.9, 156.1, 138.9, 129.9,
nicotinate (13.5 g, 98.0%). 1H NMR (400 MHz, CDCl3)
d
8.12 (br s,
127.1, 118.2, 117.2, 117.0, 108.1, 53.6, 53.2, 23.2; 19F NMR (376 MHz,
1H), 7.99 (br s, 1H), 4.02 (s, 3H), 3.90 (s, 3H), 2.29 (s, 3H). To a so-
lution of methyl 2-methoxy-5-methylnicotinate (8.65 g, 48 mmol)
in anhydrous carbon tetrachloride (80 mL) was added NBS (8.95 g,
50 mmol). The reaction mixture was heated to reflux under a UV-
lamp for 3 h. The mixture was cooled to room temperature and
concentrated. The residue was washed with hot water to remove
succinimide. The solid was purified by column (dichloromethane/
ethyl acetate 30:1) to yield methyl 5-(bromomethyl)-2-methoxy-
DMSO-d6)
d
ꢁ108; MS (ESþ) m/z: 324.89. Anal. Calcd for
C19H17FN2O2$1.5 HCl (379.36): C, 60.21; H, 4.92; N, 7.39. Found: C,
59.93; H, 4.68; N, 7.35.
4.3.29. 1-(4-Isopropoxyphenyl)-3-(2-methoxy-5-(pyrrolidin-1-
ylmethyl)pyridin-3-yl)propan-1,3-dione (A14)
To a stirred solution of compound 8 (0.50 g, 2.0 mmol) and 40-
isopropoxyacetophenone (0.37 g, 2.1 mmol) in anhydrous DMF
(10 mL) was added sodium hydride (96 mg, 2.4 mmol, 60% in
mineral oil) in small portions under nitrogen. The reaction mixture
was stirred overnight at room temperature. The reaction mixture
was stirred at 80 ꢀC for 1 h. Water (30 mL) was added and the pH
adjusted to 7 by adding acetic acid. The mixture was extracted with
chloroform (150 mL). The organic layer was washed with water
(30 mL), brine (30 mL), dried (Na2SO4), and concentrated to give
the crude title compound as a brown solid (0.66 g), which was used
nicotinate (7) (7.77 g, 62.2%). 1H NMR (400 MHz, CDCl3)
d 8.32 (d,
J¼2.34 Hz,1H), 8.21 (d, J¼2.63 Hz,1H), 4.47 (s, 2H), 4.05 (s, 3H), 3.92
(s, 3H). A mixture of compound 7 (4.4 g, 17 mmol), pyrrolidine
(4.8 g, 68 mmol) and anhydrous THF (20 mL) was heated to reflux
for 2 h, cooled to room temperature, and concentrated. The residue
was purified by column chromatography (ethyl acetate to ethyl ac-
etate/MeOH 9:1) to give methyl 2-methoxy-5-(pyrrolidin-1-ylme-
thyl)nicotinate (8) (3.50 g, 83%). 1H NMR (400 MHz, CDCl3)
d 8.23 (s,

6938
V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
in next the step without further purification. 1H NMR (400 MHz,
DMSO-d6)
1H), 6.94 (d, J¼7.42 Hz, 2H), 4.70–4.60 (m, 1H), 4.10 (s, 3H), 3.65 (s,
2H), 2.55 (br s, 4H), 1.80 (br s, 4H), 1.35 (d, J¼6.52 Hz, 6H); MS (ESþ)
m/z: 396.97 (Mþ1).
crude title compound (1.0 g, 88%). The crude product was used in
the next step without further purification. 1H NMR (400 MHz,
CDCl3) d 8.34 (br s, 1H), 8.29 (br s, 1H), 7.69 (s, 2H), 7.51–7.36 (m,
5H), 7.22 (s, 1H), 4.87 (s, 2H), 4.12 (s, 3H), 3.76 (br s, 2H), 2.69 (br s,
4H), 2.36 (s, 6H), 1.87 (br s, 4H).
d
8.29 (s, 1H), 8.22 (s, 1H), 7.94 (d, J¼7.82 Hz, 2H), 7.22 (s,
4.3.30. 2-(4-Isopropoxyphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-
pyrano[2,3-b]pyridin-4-one (B14)
4.3.34. 2-(4-Hydroxy-3,5-dimethylphenyl)-6-(pyrrolidin-1-
ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one (B16)
The title compound was synthesized following general pro-
cedure A from crude A14 (0.63 g, 1.6 mmol). The hydrochloride of
the title compound was isolated as a yellow solid (0.24 g, 41%); mp
The title compound was synthesized following general pro-
cedure A from crude A16 (1.0 g, 2.1 mmol). The hydrochloride of the
title compound was isolated as a yellow crystalline solid (0.50 g,
261–263 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
11.25 (br s, 1H), 8.98 (s,
59%); mp 337–338 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 9.28 (s, 1H),
1H), 8.73 (s,1H), 8.01 (d, J¼8.6 Hz, 2H), 7.10 (d, J¼9.0 Hz, 2H), 7.03 (s,
1H), 4.76–4.73 (s, 1H), 4.54 (s, 2H), 3.55 (br s, 2H), 3.08 (br s, 2H),
2.05 (br s, 2H), 1.85 (br s, 2H), 1.28 (d, J¼5.9 Hz, 6H); 13C NMR
9.00 (s, 1H), 8.75 (s, 1H), 7.80 (s, 2H), 7.00 (s, 1H), 4.60 (s, 2H), 3.60–
3.40 (m, 2H), 3.10 (br s, 2H), 2.25 (s, 6H), 2.05 (br s, 2H),1.85 (br s, 2H);
MS (ESþ) m/z: 351.03. Anal. Calcd for C21H22N2O3$1.5HCl (405.11): C,
62.26; H, 5.85; N, 6.91. Found: C, 61.53; H, 5.56; N, 6.88; HPLC:
95.82%. Due to lowsolubility it was not possible to record a 13C-NMR.
(100 MHz, DMSO-d6)
d 177.9, 163.9, 161.5, 160.9, 155.8, 138.8, 129.1,
122.9, 118.3, 116.6, 106.4, 70.4, 53.6, 53.3, 23.2, 22.3; MS (ESþ) m/z:
364.96 (M). Anal. Calcd for C22H24N2O3$HCl$0.6H2O (414.4): C,
63.99; H, 6.43; N, 6.78. Found: C, 63.97; H, 6.42; N, 6.74.
4.3.35. 1-(2-Methoxy-5-(morpholinomethyl)pyridin-3-yl)-3-(4-
methoxyphenyl)propane-1,3-dione (A17)
4.3.31. 1-[4-(Benzyloxy)-3,5-dimethylphenyl]-3-(5-
[(dimethylamino)methyl]-2-methoxypyridin-3-yl)propan-
1,3-dione (A15)
A mixture of compound 7 (3.0 g, 11.5 mmol) and morpholine
(4.02 g, 46.1 mmol) in anhydrous THF (15 mL) was heated to reflux
for 2 h. The reaction mixture was cooled to room temperature and
concentrated. Water and CH2Cl2 were added to the residue and the
organic layer was washed with brine, dried (Na2SO4), and con-
centrated to give methyl 2-methoxy-5-(morpholinomethyl) nic-
A mixture of compound 7 (1.0 g, 3.8 mmol) and dimethylamine
(7.7 mL, 2.0 M in THF) in dry THF (10 mL) was heated to 60 ꢀC for
4 h. The reaction mixture was cooled to room temperature, con-
centrated and purified by column chromatography (methanol/ethyl
acetate 1:3) to give 5-[(dimethylamino)methyl]-2-methox-
otinate (10) (3.0 g, 98%). 1H NMR (400 MHz, CDCl3)
d 8.20 (s, 1H),
8.10 (s, 1H), 4.10 (s, 3H), 3.90 (s, 3H), 3.70 (m, 4H), 3.50 (s, 2H), 2.40
(m, 4H). To a mixture of compound 10 (0.73 g, 2.7 mmol) and 40-
methoxy-acetophenone (0.41 g, 2.7 mmol) in anhydrous DMF was
added NaH (0.17 g, 60% in mineral oil). The reaction mixture was
kept at room temperature overnight. The mixture was poured into
water (80 mL) and the pH was adjusted to 7 by adding acetic acid.
The mixture was extracted with CH2Cl2 (3ꢂ80 mL). The combined
organic layers were washed with water, brine, dried (Na2SO4), and
concentrated to give the crude title compound (0.85 g, 81%). The
crude compound was used in the next step without further puri-
ynicotinate (9) (0.82 g, 95%). 1H NMR (400 MHz, DMSO-d6)
d 8.27
(d, J¼2.05 Hz, 1H), 8.08 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.49 (s, 2H),
2.20 (d, 6H). To a mixture of compound 9 (0.82 g, 3.7 mmol) and 1-
(4-(benzyloxy)-3,5-dimethylphenyl)ethanone.19 (0.93 g, 3.7 mmol)
in anhydrous DMF (10 mL) was added sodium hydride (0.22 g,
5.5 mmol, 60% in mineral oil). The reaction mixture was stirred
overnight at room temperature. The reaction mixture was poured
into water (150 mL) and neutralized with acetic acid. Dichloro-
methane (150 mL) was added and the organic layer was washed
with water, brine, dried (Na2SO4), concentrated, and purified by
column (ethyl acetate: methanol 8:1) to give the title compound
fication. 1H NMR (400 MHz, CDCl3)
d
8.29 (d, J¼2.34 Hz,1H), 8.20 (d,
J¼2.34 Hz, 1H), 7.98 (d, J¼9.06 Hz, 2H), 7.00 (d, J¼8.77 Hz, 2H), 4.11
(0.90 g, 55%). 1H NMR (400 MHz, CDCl3)
d
8.30 (br s, 1H), 8.24 (br s,
(s, 3H), 3.90 (s, 3H), 3.74–3.67 (m, 4H), 3.50 (s, 2H), 2.46 (br s, 4H).
1H), 7.69 (s, 2H), 7.51–7.36 (m, 5H), 7.22 (s, 1H), 4.87 (s, 2H), 4.12 (s,
3H), 3.56 (br s, 2H), 2.96 (s, 3H), 2.89 (s, 3H), 2.36 (s, 6H).
4.3.36. 2-(4-Methoxyphenyl)-6-(morpholinomethyl)-4H-
pyrano[2,3-b]pyridin-4-one (B17)
4.3.32. 6-[(Dimethylamino)methyl]-2-(4-hydroxy-3,5-
dimethylphenyl)-4H-pyrano[2,3-b]pyridin-4-one (B15)
The title compound was synthesized following general pro-
cedure A from crude A17 (0.50 g, 1.3 mmol). The reaction time was
reduced to 40 min, and the reaction was monitored by TLC. The
hydrochloride of the title compound was isolated as a yellow
crystalline solid (0.42 g, 83%); mp 307–309 ꢀC. 1H NMR (400 MHz,
The title compound was synthesized following general pro-
cedure A from crude A15 (0.80 g, 1.8 mmol). The hydrochloride of
the title compound was isolated as a yellow crystalline solid (0.40 g,
62%); mp 306–308 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
10.80 (br s,
DMSO-d6) d 11.50 (br s, 1H), 9.00 (s, 1H), 8.70 (s, 1H), 8.10 (d,
1H), 9.30 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 7.75 (s, 2H), 7.0 (s, 1H),
J¼9.06 Hz, 2H), 7.20 (d, J¼8.77 Hz, 2H), 7.10 (s, 1H), 4.55 (br s, 2H),
4.50 (s, 2H), 2.75 (s, 6H), 2.25 (s, 6H); 13C NMR (100 MHz, DMSO-d6)
4.05–3.70 (m, 7H), 3.50–3.00 (m, 4H); 13C NMR (100 MHz, DMSO-
d
178.1, 164.4, 160.8, 158.0, 156.0, 140.0, 127.6, 125.6, 122.0, 118.5,
d6) d 178.2, 164.2, 163.2, 161.1, 139.0, 129.2, 123.0, 118.3, 115.4, 106.4,
105.8, 56.0, 42.0, 17.8; MS (ESþ) m/z: 325.02. Anal. Calcd for
C19H20N2O3$HCl (360.84): C, 63.24; H, 5.87; N, 7.76. Found: C,
63.71; H, 5.76; N, 7.82.
63.9, 56.2, 51.6; MS (ESþ) m/z: 352.99. Anal. Calcd for
C20H20N2O4$HCl (388.85): C, 61.78; H, 5.44; N, 7.20. Found: C, 62.14;
H, 5.37; N, 7.37.
4.3.33. 1-[4-(Benzyloxy)-3,5-dimethylphenyl]-3-(2-methoxy-5-
[pyrrolidin-1-ylmethyl]pyridin-3-yl)propane-1,3-dione (A16)
4.3.37. 1-(4-Fluorophenyl)-3-(2-methoxy-5-(morpholinomethyl)-
pyridin-3-yl)propan-1,3-dione (A18)
To a mixture of compound 8 (0.60 g, 2.4 mmol) and 1-(4-(ben-
zyloxy)-3,5-dimethylphenyl)ethanone19 (0.61 g, 2.4 mmol) in an-
hydrous DMF (5 mL) was added sodium hydride (0.2 g, 60% in
mineral oil). The reaction mixture was kept overnight at room
temperature. The mixture was poured into water (80 mL) and the
pH was adjusted to 7 by adding acetic acid. The mixture was
extracted with CH2Cl2 (3ꢂ80 mL). The organic layer was washed
with water, brine, dried (Na2SO4) and concentrated to give the
To a mixture of compound 10 (0.51 g, 1.9 mmol) and 40-fluoro-
acetophenone (0.29 g, 2.1 mmol) in anhydrous DMF (3 mL) under
N2 was added sodium hydride (0.13 g, 3.2 mmol, 60% in mineral oil).
The mixture was stirred overnight before poured into water
(100 mL) and adjusting the pH to 7 by adding acetic acid. The
mixture was stirred for an hour and the solid was filtered off,
washed with water and hexane to give the crude title compound
(0.33 g, 47%), which was used for the next reaction without further

V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
6939
purification. 1H NMR (400 MHz, DMSO-d6)
d
8.29 (br s, 1H), 8.21 (d,
isolated as a yellow crystalline solid (0.35 g, 50%); mp >310 ꢀC
(decomposition). 1H NMR (400 MHz, DMSO-d6)
J¼1.95 Hz, 1H), 8.17–8.04 (m, 2H), 7.42 (t, J¼8.78 Hz, 2H), 4.05 (s,
d
8.76 (d, J¼3.91 Hz,
3H), 3.61–3.52 (m, 4H), 3.50 (s, 2H), 2.37 (br s, 4H).
1H), 8.25 (d, J¼8.60 Hz, 1H), 7.98 (d, J¼8.60 Hz, 2H), 7.83 (dd,
J¼8.60, 4.30 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J¼8.60 Hz, 2H); 13C NMR
4.3.38. 2-(4-Fluorophenyl)-6-(morpholinomethyl)-4H-pyrano[2,3-
b]pyridin-4-one (B18)
(100 MHz, DMSO-d6) d 176.7, 163.1, 161.9, 153.8, 148.3, 139.7, 129.2,
129.0,128.0,121.7,116.6,107.8; MS (ESþ) m/z: 239.90. Anal. Calcd for
C14H9NO4 (239.23): C, 70.29; H, 3.79; N, 5.85. Found: C, 69.16; H,
3.83; N, 5.75.
The title compound was synthesized following general pro-
cedure A from crude A18 (0.34 g, 0.9 mmol). The hydrochloride of
the title compound was isolated as a yellow crystalline solid (0.22 g,
66%); mp 298.2–298.8 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
11.21 (br
4.3.43. 1-(4-Methoxyphenyl)-3-(3-methoxypyridin-4-yl)propane-
s, 1H), 8.98 (br s, 1H), 8.76 (br s, 1H), 8.31–8.16 (m, 2H), 7.48 (t,
J¼8.80 Hz, 2H), 7.21 (s, 1H), 4.57 (br s, 2H), 3.97 (br s, 2H), 3.74 (br s,
2H), 3.32 (br s, 2H), 3.16 (br s, 2H); 13C NMR (100 MHz, DMSO-d6)
1,3-dione (12)
To
a
mixture of methyl 3-fluoroisonicotinitate21 (3.50 g,
22.7 mmol) and 40-methoxyacetophenone (3.60 g, 24 mmol) in dry
DMF (10 mL) under nitrogen was added sodium hydride (1.82 g,
60% in mineral oil). The reaction mixture was stirred for half hour
then poured into an ammonium chloride solution and extracted
with ethyl acetate. The organic layer was dried (Na2SO4), concen-
trated, and purified by column chromatography (ethyl acetate/
hexane 1:3) to give the title compound (3.5 g, 54%), which was used
d
178.2, 166.3, 163.8, 162.9, 161.1, 139.9, 130.0, 127.8, 125.0, 118.2,
117.7, 116.7, 107.7, 107.5, 63.7, 55.9; 19F NMR (376 MHz, DMSO-d6)
d
ꢁ107.8; MS (ESþ) m/z: 364.96 (M). Anal. Calcd for
C19H17FN2O3$HCl (376.82): C, 60.56; H, 4.81; N, 7.43. Found: C,
60.40; H, 4.31; N, 7.44.
4.3.39. 1-(4-[Benzyloxy)phenyl]-3-(2-methoxy-5-
without further purification. 1H NMR (400 MHz, CDCl3)
d 8.47 (s,
(morpholinomethyl)pyridin-3-yl)propan-1,3-dione (A19)
1H), 8.40 (d, J¼4.97 Hz, 1H), 7.97 (d, J¼9.06 Hz, 2H), 7.77 (d,
J¼4.97 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J¼8.77 Hz, 2H), 4.08 (s, 3H), 3.89
(s, 3H).
To a mixture of compound 10 (0.81 g, 3.0 mmol) and 40-benzy-
loxyacetophenone (0.70 g, 3.0 mmol) in anhydrous DMF (5 mL) was
added sodium hydride (0.18 g, 60% in mineral oil). The reaction
mixture was kept overnight at room temperature before poured
into water (80 mL) and adjusting the pH to 7 by adding acetic acid.
The mixture was extracted with CH2Cl2 (3ꢂ80 mL). The combined
organic layers were washed with water, brine, dried (Na2SO4), and
concentrated to give the crude compound (0.13 g, 94%), which was
4.3.44. 2-(4-Hydroxyphenyl)-4H-pyrano[2,3-c]pyridin-4-one (B21)
The title compound was synthesized following general pro-
cedure A from crude 12 (0.50 g, 1.8 mmol). The title compound was
isolated as a yellow crystalline solid (0.36 g, 86%); mp 294–296 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
10.42 (br s, 1H), 9.16 (s, 1H), 8.62 (d,
used without further purification. 1H NMR (400 MHz, CDCl3)
d 8.29
(d, J¼2.35 Hz, 1H), 8.20 (d, J¼2.35 Hz, 1H), 7.97 (d, J¼9.09 Hz, 2H),
7.49–7.33 (m, 5H), 7.25 (s, 1H), 7.05 (m, 2H), 5.16 (s, 2H), 4.11 (s, 3H),
3.74–3.66 (m, 4H), 3.50 (s, 2H), 2.46 (br s, 4H).
J¼3.81 Hz, 1H), 7.97 (d, J¼7.62 Hz, 2H), 7.85 (d, J¼3.81 Hz, 1H), 7.08–
6.85 (m, 3H); 13C NMR (101 MHz, DMSO-d6)
d 176.5, 164.4, 162.1,
151.7, 145.8, 142.9, 129.3, 128.5, 121.7, 117.7, 116.7, 106.4; MS (ESþ) m/
z: 239.89. Anal. Calcd for C14H9NO4 (239.23): C, 70.29; H, 3.79; N,
5.85. Found: C, 70.12; H, 3.78; N, 5.88.
4.3.40. 2-(4-Hydroxyphenyl)-6-(morpholinomethyl)-4H-
pyrano[2,3-b]pyridin-4-one (B19)
4.3.45. 1-[4-(Benzyloxy)phenyl]-3-(4-methoxypyrimidin-5-
yl)propane-1,3-dione (13)
The title compound was synthesized following general pro-
cedure A from crude A19 (1.30 g, 2.8 mmol). The title compound
was isolated as a yellow crystalline solid (0.54 g, 57%); mp 232–
To a solution of methyl 4-methoxypyrimidine-5-carboxylate22
(0.41 g, 2.44 mmol) and 40-benzyloxyacetophenone (0.58 g,
2.6 mmol) in anhydrous DMF (10 mL) was added sodium hydride
(117 mg, 2.93 mmol, 60% suspension in mineral oil) in small por-
tions. The reaction mixture was stirred at room temperature un-
der nitrogen for 30 min, then at 80 ꢀC for 3 h. The reaction
mixture was cooled to room temperature and a saturated aqueous
ammonium chloride solution (100 mL) was added. The mixture
was extracted with ethyl acetate (2ꢂ100 mL). The combined or-
ganic layers were washed with water (100 mL), brine (100 mL),
dried (Na2SO4), and concentrated. The crude product was purified
by column chromatography (Silica Gel 230–400 mesh; 10–20%
ethyl acetate in hexanes as eluent) to give the title compound as
234 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 10.39 (s, 1H), 8.69 (d,
J¼2.34 Hz, 1H), 8.37 (d, J¼1.46 Hz, 1H), 7.97 (d, J¼8.77 Hz, 2H), 6.96
(m, 3H), 3.66 (s, 2H), 3.59 (t, J¼4.24 Hz, 4H), 2.41 (br s, 4H); 13C NMR
(100 MHz, DMSO-d6)
d 178.2, 164.1, 161.9, 160.1, 154.2, 136.1, 133.1,
129.2, 121.8, 118.1, 116.7, 105.7, 66.8, 59.1, 53.6; MS (ESþ) m/z 339.15
(Mþ1). Anal. Calcd for C19H18N2O4: C, 66.44; H, 5.36; N, 8.28.
Found: C, 66.32; H, 5.38; N, 7.49.
4.3.41. 1-(4-Methoxyphenyl)-3-(3-methoxypyridin-2-yl)propan-
1,3-dione (11)
To a mixture of sodium hydride (1.62 g, 40 mmol, 60% in mineral
oil) and methyl 3-methoxypicolinate20 (3.5 g, 20 mmol) in anhy-
a yellow solid (0.45 g, 51%). 1H NMR (400 MHz, DMSO-d6)
d 9.03
drous DMF (20 mL) was added
a
solution of 40-methoxy-
(s, 1H), 8.95 (s, 1H), 8.05 (d, J¼8.97 Hz, 2H), 7.53–7.31 (m, 5H),
7.24–7.16 (m, 3H), 5.25 (s, 2H), 4.13 (s, 3H); MS (ESþ) m/z: 362.89
(Mþ1).
acetophenone (3.3 g, 22 mmol) via syringe. The reaction mixture
was stirred overnight at room temperature, then a 10% aqueous so-
lution of NaH2SO4 was used to adjust the pH to 7. The mixture
was extracted with ethyl acetate. The combined organic layers
were dried (Na2SO4), concentrated, and purified by column chroma-
tography using 30% ethyl acetate in hexaneto give the title compound
(4.68 g, 80%), which was used without further purification. 1H NMR
4.3.46. 7-(4-Hydroxyphenyl)-5H-pyrano[2,3-d]pyrimidin-
5-one (B22)
The title compound was synthesized following general pro-
cedure A from crude 13 (0.415 g, 1.15 mmol). The title compound
was isolated as a yellow crystalline solid (0.035 g, 13%); mp 311–
(400 MHz, CDCl3)
d 8.38–8.31 (m, 1H), 8.02–7.96 (m, 2H), 7.44–7.38
(m, 2H), 7.12 (s, 1H), 6.96 (d, J¼8.99 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H).
313 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
10.50 (br s, 1H), 9.35 (s, 1H),
9.30 (s, 1H), 7.95 (d, J¼8.95 Hz, 2H), 7.05 (s, 1H), 6.90 (d, J¼8.95 Hz,
4.3.42. 2-(4-Hydroxyphenyl)-4H-pyrano[3,2-b]pyridin-
4-one (B20)
The title compound was synthesized following general pro-
cedure A from crude 11 (0.83 g, 3.5 mmol). The title compound was
2H); 13C NMR (100 MHz, DMSO-d6)
d 177.1, 166.1, 164.4, 162.3, 161.8,
158.1, 129.4, 121.2, 116.8, 116.5, 107.6; MS (ESþ) m/z: 240.78 (M).
Anal. Calcd for C13H8N2O3 (240.21): C, 65.00; H, 3.36; N, 11.66.
Found: C, 64.24; H, 3.13; N, 11.13.

6940
V. Khlebnikov et al. / Tetrahedron 65 (2009) 6932–6940
9. Cyclization of flavonoids from already deprotected dibenzoylmethanes have
Supplementary data
previously been described: Makrandi, J. K.; Sharma, A. K.; Kumar, S. Indian J.
Heterocycl. Chem. 2005, 14, 275–276.
NMR spectra for all final products are available. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2009.06.062.
10. General procedure: Compound A was mixed with pyridinium hydrocloride
(10 equiv) and heated to 190 ꢀC for 1–4 h. The reaction was followed by TLC and
worked-up once all of the starting material was consumed.
11. Yao, N.; Song, A.; Wang, X.; Dixon, S.; Lam, K. S. J. Comb. Chem. 2007, 9, 668–676.
12. Hardegger, E.; Nikles, E. Helv. Chim. Acta 1956, 39, 505–513.
13. Shimizu, K.; Sakamoto, I.; Fukushima, S. Yakugaku Zasshi 1967, 87, 672–676.
14. Noller, C. R.; Adams, R. J. Am. Chem. Soc. 1924, 46, 1889–1896.
15. Leopold, B. Acta Chem. Scand. 1950, 4, 1523–1537.
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