A synthesis of the pyrano[3,2-b]pyridine ring system under mild conditions

Article abstract of DOI:10.1081/SCC-100000577

A route to the relatively rare pyrano[3,2-b]pyridin-4-one template (1) is described starting from 3-hydroxypyridine. This synthesis allows for varying the substituents at the 2- and 3-positions of the bicycle. A diisopropylsilyloxy moiety was employed to

Full text of DOI:10.1081/SCC-100000577

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A SYNTHESIS OF THE PYRANO[3,2-b]PYRIDINE RING
SYSTEM UNDER MILD CONDITIONS
Lalgudi S. Harikrishnan , Terri L. Boehm & H. D. Hollis Showalter
To cite this article: Lalgudi S. Harikrishnan , Terri L. Boehm & H. D. Hollis Showalter (2001)
A SYNTHESIS OF THE PYRANO[3,2-b]PYRIDINE RING SYSTEM UNDER MILD CONDITIONS,
Synthetic Communications, 31:4, 519-525, DOI: 10.1081/SCC-100000577
To link to this article: http://dx.doi.org/10.1081/SCC-100000577
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SYNTHETIC COMMUNICATIONS, 31(4), 519–525 (2001)
A SYNTHESIS OF THE
PYRANO[3,2-b]PYRIDINE RING SYSTEM
UNDER MILD CONDITIONS
Lalgudi S. Harikrishnan,∗ Terri L. Boehm,
and H. D. Hollis Showalter
Chemistry Department, Pfizer Global Research and
Development, Ann Arbor Laboratories, 2800 Plymouth
Road, Ann Arbor, Michigan 48105, USA
ABSTRACT
A route to the relatively rare pyrano[3,2-b]pyridin-4-one tem-
plate (1) is described starting from 3-hydroxypyridine. This synthe-
sis allows for varying the substituents at the 2- and 3-positions of
the bicycle. A diisopropylsilyloxy moiety was employed to direct
lithiation of a pyridine intermediate to the less favored 2-position.
Benzopyranones are pharmacologically important compounds that exhibit
a variety of biological activities (1–5). Owing to their poor solubility in water,
appropriate solubilizing and suspending agents have to be employed in order for
them to be useful pharmacologic agents. Simple aza congeners such as pyrano[3,2-
b]pyridin-4-ones (and their salts) may serve to circumvent solubility liabilities, due
to their higher hydrophilicity. In this paper, we describe a relatively straightforward
synthesis to this relatively rare ring system, which is amenable for introduction of
substituents at the 2- and 3-positions.
∗Corresponding author. Current address: Bristol-Myers Squibb Company, Mail Stop L13-
14, P.O. Box 4000, Princeton, NJ 08543-4000. E-mail: lalgudi.harikrishnan@bris.com
519
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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HARIKRISHNAN, BOEHM, AND SHOWALTER
In spite of the spectrum of activities (antiallergy (6), bronchodialating (7),
antiulcer (8), selective chronotropic negative (9) activities) exhibited by com-
pounds with the pyrano[3,2-b]pyridin-4-one core structure, there are no reports
on the synthesis of 2,3-disubstituted pyrano[3,2-b]pyridin-ones 1. However, the
synthesis of 2,3-benzo-fused and 3-aryl pyrano[3,2-b]pyridines is known. Further-
more, regardless of the substitution pattern, the synthesis of known pyrano[3,2-
b]pyridin-4-one skeleta requires harsh acidic conditions in the ring forming step
(typically refluxing acetic (10) or formic acid (6), or hot polyphosphoric acid (7)).
Hence, methodology to synthesize this template under milder conditions would be
of considerable utility. Therefore, our objective was to develop such conditions as
part of an efficient route to this rare template.
Retrosynthetically, 2,3-disubstituted pyrano[3,2-b]pyridin-4-ones can be
thought of as being derived from the aldehyde 3 (Scheme 1). The substituent
at the 3-position can be introduced by Grignard reagents, while that at the 2-
position can be derived from amide acetals or ortho esters. The aldehyde 3 can
be obtained by ortho formylation of a suitably protected 3-hydroxypyridine. The
reduction of this logic to practice is shown is Scheme 2. 3-Hydroxy pyridine 4 was
protected as its MOM ether 5 (11). Preliminary CD3OD quench studies indicated
that reaction of compound 5 with t-BuLi in THF or ether gave exclusive lithia-
tion at the 4-position. Hence, the 4-position was blocked as a silyl ether to direct
subsequent lithiation to the 2-position. The benzyloxy diisopropyl silyl group was
chosen over the more conventional trialkyl silyl moiety in the event we decided at
a later stage to apply our methodology to the solid phase utilizing our previously
described traceless silyl linker (12). Here the benzyloxy group would serve as a
surrogate for polystyrene hydroxymethyl resin. Thus, compound 5 was lithiated
selectively at the 4-position and quenched with dichlorodiisopropyl silane, fol-
lowed by reaction with benzyl alcohol to give the silyl ether 6. Ortho lithiation of
compound 6, followed by quenching the anion with DMF, afforded the aldehyde
7. Addition of benzylmagnesium chloride to aldehyde 7, followed by IBX oxida-
tion, yielded ketone 8. The MOM ether in compound 8 was removed selectively
without affecting the silyl group by treatment with 20% TFA in dichloromethane
at 0◦C for 1 h. Longer reaction times at 25◦C with lower concentrations of TFA led
R2
RO
RO
SiR3
N
SiR3
R2
R1
O
O
R2
R1
OH
NR2
OH
O
H
N
N
N
XMg
O
1
O
R1
2
3
R1 = aryl; R2 = alkyl
Scheme 1.

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PYRANO[3,2-b]PYRIDINE RING SYSTEM
521
e, f, g
b, c, d
h, i
4 R = H
6
7
a
5 R = MOM
k
10
11
8 R = MOM
9 R = H
j
a. MOMCl, Hunigs base, CH2Cl2. b. t-BuLi, THF, −78°C. c. iPr2SiCl2, −78°C to 25°C.
d. BnOH, Imidazole, DMF. e. n-BuLi, TMEDA, THF, −78°C. f. DMF, −78°C −
0°C. g.
sat. aq. NH4Cl. h. BnMgCl, THF, 0°C. i. IBX, DMSO, 25°C. j. 20% TFA/DCM, 0°C. k.
MeC(OMe)2NMe2, THF, 35°C. I. TBAF/THF.
Scheme 2.
to competitive cleavage of the silyloxy group to yield the corresponding silanol.
Treatment of compound 9 with N,N-dimethylacetamide dimethyl acetal in THF
gave the pyranone 10. The silyl group was cleaved cleanly with TBAF to obtain
the target pyrano[3,2-b]pyridin-4-one 11.
In summary, we have designed an efficient route to the synthesis of 2,3-
disubstituted pyrano[3,2-b]pyridin-4-ones under mild conditions. Extensions of
this methodology promise facile access to other heterobicycles containing the 2,3-
fused pyridine nucleus.
EXPERIMENTAL
Materials and Methods
Standard reagents were obtained from commercial suppliers and used with-
out further purification. Column chromatography was carried out using E. Merck
60 (230–400 mesh) silica gel. Thin layer chromatography was performed us-
1
ing Merck 60 F254 0.25 µm silica gel plates. H and 13C NMR spectra were
obtained on a Varian Unity 400 MHz spectrometer at 400 MHz and 101 MHz,

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HARIKRISHNAN, BOEHM, AND SHOWALTER
respectively. Spectra were obtained in CDCl3 with TMS as the internal standard
and are reported in ppm. Atmospheric pressure chemical ionization mass spectra
(APCIMS) were recorded using a VG Trio 2000 mass spectrometer in a matrix of
MeOH/CH3CN/DMSO. Following normal work-up procedures, organic extracts
were dried over anhydrous Na2SO4 prior to concentration.
4-(Benzyloxy-diisopropyl-silanyl)-3-methoxymethoxy-pyridine 6
To a solution of 3-methoxymethoxy-pyridine 5 (11) (5.0 g, 35.9 mmol) in
anhydrous diethyl ether (125 mL) at −78◦C was added dropwise t-BuLi (1.7 M
in pentane, 23.2 mL, 39.4 mmol). A white precipitate was formed during the
addition. The mixture was stirred for 15 min at −78◦C and dichlorodiisopropyl
silane (7.1 mL, 39.4 mmol) was added quickly. The mixture was gradually warmed
to 25◦C and stirred for 9 h. DMF (15 mL) was added to the mixture, which was then
concentrated to remove volatiles. To the solution of crude chlorosilane in DMF
was added imidazole (4.2 g, 61.7 mmol), followed by benzyl alcohol (4.1 mL,
39.4 mmol), and the mixture was stirred at 25◦C for 4 h. The mixture was diluted
with ether (250 mL) and washed with water (3 × 250 mL), followed by brine
(100 mL). The ether phase was dried, concentrated, and chromatographed on
300 g of SiO2, eluting with 20:1 then 10:1 Hex:EtOAc, to give the silyl ether 6
(6.8 g, 52%) as a colorless oil, Rf ∼ 0.2 (10:1, Hex:EtOAc). The material was
pure by NMR and mass spectrometry, and was suitable for direct use in the next
reaction. 1H NMR δ 8.44 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 4.4 Hz,
1H), 7.38–7.31 (m, 4H), 7.24 (t, J = 7.1 Hz, 1H), 5.14 (s, 2H), 4.92 (s, 2H), 3.42
(s, 3H), 1.38 (sep, J = 7.4 Hz, 2H), 1.05 (d, J = 7.3 Hz, 6H), 1.00 (d, J = 7.6
Hz); 13C NMR δ 157.6, 142.9, 140.9, 135.1, 132.7, 130.4, 128.3, 127.0, 125.8,
94.4, 65.6, 56.2, 17.6, 17.4, 12.7; APCIMS m/z: 360.1 (MH+, 100%).
4-(Benzyloxy-diisopropyl-silanyl)-3-methoxymethoxy-pyridine-2-
carbaldehyde 7
To a solution of silyl ether 6 (6.0 g, 16.6 mmol) in anhydrous diethyl ether
(100 mL) at −78◦C was added TMEDA (6.3 mL, 41.5 mmol), followed by
n-BuLi (1.6 M in hexanes, 20.8 mL, 33.2 mmol). The mixture was stirred at
−78◦C for 30 min. Anhydrous DMF (11.4 mL, 83.0 mmol) was added and the
mixture was allowed to warm to 0◦C, and then stirred for 1 h. The mixture was
diluted with sat. aq. NH4Cl (10 mL), stirred at 0◦C for 30 min and then at 25◦C
for 30 min, and extracted with ether (200 mL). The ether extract was washed with
water (3 × 200 mL), then brine (1 × 100 mL), and concentrated to an oil that
was chromatographed (Hex:EtOAc) to leave aldehyde 7 (3.5 g, 55%) as a yellow

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523
oil. 1H NMR δ 10.2 (s, 1H), 8.53 (d, J = 4.3 Hz, 1H), 7.70 (d, J = 4.3 Hz, 1H),
7.40–7.27 (m, 5H), 5.10 (s, 2H), 4.96 (s, 2H), 3.52 (s, 3H), 1.46 (sep, J = 7.5 Hz,
2H), 1.13 (d, J = 7.3 Hz, 6H), 1.05 (d, J = 7.5 Hz, 6H); 13C NMR δ 191.9, 159.0,
144.7, 143.6, 141.1, 140.6, 135.6, 128.4, 127.3, 126.0, 101.1, 65.9, 58.0, 17.8,
17.5, 12.9; APCIMS m/z: 388.1 (MH+, 100%).
1-[4-(Benzyloxy-diisopropyl-silanyl)-3-methoxymethoxy-pyridin-2-yl]-2-
phenyl-ethanone 8
To a solution of benzylmagnesium chloride (2.0 M in THF, 7.7 mL,
15.4 mmol) in THF (30 mL) at 0◦C was added dropwise a solution of aldehyde 7
(3.0 g, 7.7 mmol) in THF (30 mL). The mixture was gradually warmed to 25◦C,
stirred for 30 min, and again cooled to 0◦C. The reaction mixture was carefully
quenched with water (5 mL) and extracted with ether (250 mL). The ether extract
was washed with water (2 × 200 mL) and then sat. aq. NH4Cl (1 × 100 mL),
dried, and concentrated to a residue that was chromatographed to afford purified
intermediate alcohol. To the alcohol (2.6 g, 5.4 mmol) was added a solution of IBX
(6.1 g, 21.7 mmol) in DMSO (75 mL) and the mixture was stirred at 25◦C for 2 h.
Water (150 mL) was added to the mixture and the precipitated solid was filtered
off and washed with water. The filtrate was extracted with ether (150 mL) and
then the extract was washed successively with 100-mL portions of water, sat. aq.
NaHCO3, water, and brine. The ether phase was dried and concentrated to leave
ketone 8 (2.2 g, 60% from aldehyde 7) as a pale yellow oil. 1H NMR δ 8.37 (d, J =
4.3 Hz, 1H), 7.64 (d, J = 4.3 Hz, 1H), 7.42–7.22 (m, 10H), 4.96 (s, 2H), 4.89(s,
2H), 4.49 (s, 2H), 3.30 (s, 3H), 1.43 (sep, J = 7.5 Hz, 2H), 1.12 (d, J = 7.5 Hz,
6H), 1.04 (d, J = 7.5 Hz, 6H); 13C NMR δ 200.1, 155.7, 145.7, 142.3, 140.8,
139.9, 134.7, 133.9, 130.2, 128.4, 127.2, 126.7, 125.9, 99.1, 65.8, 57.4, 46.9, 17.8,
17.6, 12.9; APCIMS m/z: 478.2 (MH+, 100%).
1-[4-(Benzyloxy-diisopropyl-silanyl)-3-hydroxy-pyridin-2-yl]-2-phenyl-
ethanone 9
To a vigorously stirred solution of ketone 8 (0.2 g, 0.42 mmol) in dichloro-
methane, cooled to 0◦C, was added TFA (2.0 mL), and the mixture was stirred
for 1.5 h. The mixture was diluted with cold dichloromethane (10 mL), and the
solution was washed carefully with cold 5% aq. NaHCO3 (4 × 20 mL). The organic
phase was dried and concentrated to a residue that was chromatographed (25:1,
1
Hex:EtOAc) to give the hydroxypyridine 9 (0.162 g, 89%) as an oil. H NMR
δ 12.09 (s, 1H), 8.28 (d, J = 4.2 Hz, 1H), 7.70 (d, J = 4.4 Hz, 1H), 7.44–7.24

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HARIKRISHNAN, BOEHM, AND SHOWALTER
(m, 10H), 4.99 (s, 2H), 4.63 (s, 2H), 1.50 (sep, J = 7.6 Hz, 2H), 1.11 (d, J =
7.6Hz, 6H), 1.07(d, J = 7.3Hz, 6H);13CNMRδ 206.8, 163.0, 140.9, 140.4, 137.4,
135.1, 134.6, 134.4, 130.1, 128.5, 128.4, 127.2, 126.9, 126.0, 65.8, 43.9, 17.6, 17.4,
12.7; APCIMS m/z: 434.2 (MH+, 100%); Anal. calcd. for C26H31NO3Si: C, 72.02;
H, 7.21; N, 3.23. Found: C, 72.12; H, 7.04; N, 3.15.
8-(Benzyloxy-diisopropyl-silanyl)-2-methyl-3-phenyl-pyrano[3,2-b]-
pyridin-4-one 10
To a solution of the hydroxypyridine 9 (100 mg, 0.23 mmol) in anhy-
drous THF (1 mL) was added N,N-dimethylacetamide dimethyl acetal (0.14 mL,
0.92 mmol). The mixture was stirred for 12 h at 35◦C. The solvent was removed
by concentration and the crude product was chromatographed (1:1, Hex:EtOAc)
to give the pyranone 10 (96 mg, 91%) as an oil. 1H NMR δ 8.77 (d, J = 4.2 Hz,
1H), 7.80 (d, J = 4.2 Hz, 1H), 7.44–7.23 (m, 10H), 4.98 (s, 2H), 2.24 (s, 3H),
1.53 (sep, J = 7.4 Hz, 2H), 1.12 (d, J = 7.3 Hz, 6H), 1.07 (d, J = 7.5 Hz, 6H);
13C NMR δ 176.1, 162.5, 156.4, 147.5, 140.3, 138.4, 135.9, 134.6, 132.5, 130.4,
128.5, 128.4, 128.1, 127.4, 126.1, 125.9, 66.1, 19.3, 17.6, 17.3, 12.9; HRMS m/z
calc. 458.2151 (MH+), found: 458.2153.
2-Methyl-3-phenyl-pyrano[3,2-b]pyridin-4-one 11
To pyranone 10 (22.5 mg, 0.05 mmol) was added a solution of TBAF
(1.0 M in THF, 0.15 mL, 0.15 mmol) and the mixture was stirred for 2 min
at 25◦C. Water (5 mL) was added and the solution was extracted with CHCl3
(2 × 10 mL). The combined extracts were washed with water (3 × 5 mL) and then
brine (1 × 5 mL). The organic phase was dried and concentrated to a residue that
was chromatographed (EtOAc) to give the pyranopyridinone 10 (9.0 mg, 76%)
1
as a colorless crystalline solid. Mp 150◦–153◦C; H NMR δ 8.83 (m, 1H), 7.85
(d, J = 8.4 Hz, 1H), 7.62 (m, 1H), 7.47–7.25 (m, 5H), 2.34 (s, 3H); 13C NMR
δ 175.5, 163.1, 152.9, 147.9, 139.2, 132.5, 130.3, 128.5, 128.1, 127.5, 126.7,
126.1, 19.5; HRMS m/z calc. 238.0868 (MH+), found: 238.0865; Anal. calcd for
C15H11NO2·0.3H2O: C, 74.25; H, 4.82; N, 5.77. Found: C, 73.99; H, 4.93; N, 5.60.
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Received in the USA May 10, 2000

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