5-Amino-2H-pyran-3(6H)-one, 1, a Convenient Intermediate in the Synthesis of Pyran Containing 1,4-Dihydropyridines

Article abstract of DOI:10.1081/SCC-120027702

5-Amino-2H-pyran-3(6H)-one, 1, is a novel intermediate that is useful in the synthesis of pyran containing dihydropyridines. The synthesis and use of 1 will be discussed.

Full text of DOI:10.1081/SCC-120027702

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5‐Amino‐2H‐pyran‐3(6H)‐one, 1, a Convenient
Intermediate in the Synthesis of Pyran Containing
1,4‐Dihydropyridines
Robert J. Altenbach a , Konstantinos Agrios a , Irene Drizin a & William A. Carroll a
a Abbott Laboratories, Neuroscience Research , Global Pharmaceutical Research and
Development , Dept R4MN, Bldg AP9A, 100 Abbott Park Rd., Abbott Park, Illinois,
60064‐6123, USA
Published online: 16 Aug 2006.
To cite this article: Robert J. Altenbach , Konstantinos Agrios , Irene Drizin & William A. Carroll (2004)
5‐Amino‐2H‐pyran‐3(6H)‐one, 1, a Convenient Intermediate in the Synthesis of Pyran Containing 1,4‐Dihydropyridines,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:4,
557-565, DOI: 10.1081/SCC-120027702
To link to this article: http://dx.doi.org/10.1081/SCC-120027702
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 4, pp. 557–565, 2004
5-Amino-2H-pyran-3(6H)-one, 1,
a Convenient Intermediate in the
Synthesis of Pyran Containing
1,4-Dihydropyridines
*
Robert J. Altenbach, Konstantinos Agrios, Irene Drizin,
and William A. Carroll
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical
Research and Development, Abbott Park, Illinois, USA
ABSTRACT
5-Amino-2H-pyran-3(6H)-one, 1, is a novel intermediate that is useful in
the synthesis of pyran containing dihydropyridines. The synthesis and use
of 1 will be discussed.
Key Words: 5-Amino-2H-pyran-3(6H)-one; Pyran; Dihydropyridines;
Potassium channel blockers; Enamine.
*
Correspondence: Robert J. Altenbach, Abbott Laboratories, Neuroscience Research,
Global Pharmaceutical Research and Development, Dept R4MN, Bldg AP9A,
100 Abbott Park Rd., Abbott Park, IL 60064-6123, USA; E-mail: robert.j.altenbach@
abbott.com.
557
DOI: 10.1081/SCC-120027702
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Altenbach et al.
Figure 1. Structures of enamine 1 and DHPs 2 and 3.
1,4-Dihydropyridines (DHPs) such as nifedipine are well known to have
activity as calcium channel blockers. Recently, the acridinedione ZM244085,
2, was reported as an ATP sensitive potassium (KATP) channel opener without
calcium channel blocking activity (see Fig. 1).[1] During structure activity
relationship studies investigating KATP channel openers for the treatment of
overactive bladder, we discovered a series of novel pyran containing DHPs
represented by structure 3.[2] Enamine 1 was found to be a useful intermediate
for the synthesis of this series. The synthesis and use of 1 to generate a wide
range of pyran containing DHPs will be discussed.
Our synthesis of enamine 1 is shown in Sch. 1. A crucial intermediate for
the synthesis of 1 as well as the pyran containing DHP series was pyran-3,5-
dione, 6. The reported synthesis of intermediate ketone 5 and cyclization to 6
by Teresawa and Okada was found to be inconvenient for larger scale.[3]
A
modification of a procedure reported by Morgan and Van Heyningen was used
to generate 5.[4] Propargyl alcohol was deprotonated with sodium hydride in
THF and alkylated with methyl bromoacetate to provide acetylene 4 in 52%
yield after distillation. Hydration of 4 catalyzed by mercury(II) acetate
provided after distillation a 55% yield of ketone 5. Conditions similar to those
used by Ziegler and Bennett to synthesize 1-benzylpiperidine-3,5-dione were
used to cyclize 5 to 6.[5] The dropwise addition of 5 as a solution in ether to a
mixture of potassium tert-butoxide in anhydrous ether provided, after
Scheme 1.

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5-Amino-2H-pyran-3(6H)-one
559
Scheme 2.
crystallization, a 31% yield of pure 6. A synthesis of 6, amenable to large
scale, has recently been reported.[6]
We were unsuccessful at converting 6 directly into 1 under conditions
which have been reported for the conversion of cyclohexane-1,3-dione to
3-aminocyclohex-2-enone.[7] Cyclopenten-1,3-dione, a molecule similar to 6
in that it is also relatively resistant to direct incorporation of ammonia, was
successfully converted via an intermediate ethyl vinyl ether to the corres-
ponding enaminone by Kikani et al.[8] This modification proved beneficial to
us. Vinyl ether 7 was obtained by stirring 6 in ethanol in the presence of
sulfuric acid at ambient temperature over night followed by a basic workup.
Treatment of 7 with ammonia in ethanol at room temperature provided
enaminone 1 in 77% overall yield from 6.
The formation of symmetrical pyran 3 was examined using enamine 1.[9]a
Heating a mixture of 1, 6 and 3-bromo-4-fluorobenzaldehyde 8 in ethanol for
60 hours provided a 10 : 1 mixture of 3 and pyran 9b (Sch. 2). Repeating this
reaction with 0.5 equivalents of triethylamine provided pure 3 in 52%.
Enamine 1 was found useful for synthesizing a variety of novel
nonsymmetrical pyran containing DHPs. Reaction of cyclic 1,3-diones and b-
keto sulfones of structure 10 with 1 in the presence of 8 provided ketone and
sulfone containing DHPs respectively of general structure 12 (see Sch. 3 and
Table 1). The addition of 0.5 equivalents of triethylamine to these Hantzsch
reactions was beneficial in most cases by reducing the formation of sym-
metrical DHP 3 that complicated the purification of the nonsymmetrical
aWe found that the DHP 3 could be obtained in only 33% by the method reported for
the synthesis of 2.
bCompound 9 was independently synthesized and isolated as a solid in 63% yield by
heating two equivalents of 6 with one equivalent of 8 in EtOH for 60 hours at 808C in a
seated vessel. MS (DCI) m/z 412 (M þ H)þ; 1H NMR (DMSO-d6) d 4.14 (s, 4H), 4.60
(AB quart, 4H), 4.63 (s, 1H), 7.31 (m, 2H), 7.54 (dd, 1H).

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Altenbach et al.
Scheme 3.
DHPs. Triethylamine is believed to be acting as an acid scavenger and thus
reducing the conversion of 1 to 6. The presence of 6 presumably results in the
undesired Hantzsch reaction between 1, 6 and 8 that leads to the formation of 3.
The hemiaminal of structure 11 is believed to be an intermediate in the
Hantzsch reaction involving 1. In the case of sulfone 10a, hemiaminal 11a was
the major product from the Hantzsch reaction. The presence of the
triethylamine had prevented the in situ acid catalyzed dehydration of the
hemiaminal to the DHP from occurring. Compound 11a was smoothly
converted to DHP 12a by briefly heating in ethanol in the presence of HCl.
The hemiaminal intermediates of DHPs possessing two carbonyl function-
alities in conjugation with the DHP core were not isolated in the presence of
triethylamine. Instead, the desired DHPs were obtained as a crystalline solid
directly from the reaction mixtures.
As mentioned above, triethylamine was not beneficial in every case.
Examples 10b and 10c provided low yields and complex reaction mixtures
Table 1. Pyran containing DHPs.
Compound
X
Y
m
n
Producta
Yield (%)
10a[10]
10b[10]
10c
SO2
SO2
CH2
CH2
CH2
CH2
NH
NBn
S
0
1
0
1
0
1
1
1
1
1
1
1
2
1
1
1
12ab
12bc
12cd
12d
12ec
12fe
12g
3
59
77
32
48
52
39
39
52
C55O
C55O
C55O
C55O
C55O
C55O
10d
10e[11]
10f[5]
10g[12]
6
O
aUnless noted otherwise, products were collected by filtration directly from the reaction
mixture.
bHemiaminal of structure 10a was isolated.
cTriethylamine was not used.
dAmmonium acetate used in place of triethylamine.
eProduct was purified by chromatography.

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5-Amino-2H-pyran-3(6H)-one
561
using triethylamine. In the case of 10b, the use of no base provided the highly
crystalline12b in 77%. Ammonium acetate in place of triethylamine proved
beneficial in the case of 10c wherein 12c was isolated pure in 32%.
Compound 1 is a useful reagent for generating pyran containing DHPs.
We have demonstrated its use for generating both symmetrical as well as
nonsymmetrical pyran containing DHPs.
EXPERIMENTAL
Proton NMR spectra were obtained on a General Electric QE 300 MHz
instrument with chemical shifts (d) reported relative to tetramethylsilane as an
internal standard. Melting points were determined on a Thomas–Hoover
capillary melting point apparatus and are uncorrected. Elemental analyses
were performed by Robertson Microlit Laboratories. Thin layer chromatog-
raphy (TLC) was performed using 250 mm silica gel 60 glassbacked plates
with F254 as indicator.
Methyl propynyloxyacetate (4). A mechanically stirred suspension of
sodium hydride (60% dispersion in mineral oil) (50 g, 1.25 mol) in
tetrahydrofuran (800 mL) at 08C under nitrogen was treated dropwise with a
solution of propargyl alcohol (84 g, 1.5 mol) in tetrahydrofuran (175 mL),
stirred at 08C for 1 hour, treated with a solution of methyl bromoacetate
(199 g, 1.3 mol) in tetrahydrofuran (250 mL) over 15 minutes, stirred at 08C
for 30 minutes, stirred at ambient temperature for 2 hours, and treated with
2 M HCl (800 mL). The organic layer was isolated and the aqueous layer was
extracted with ethyl acetate (2 Â 500 mL). The combined organic layers were
washed with brine (200 mL), dried (MgSO4), filtered, concentrated and
1
distilled (bp 75 2 858C at 20 torr) to provide 83 g (52%) of 4: H NMR
(CDCl3) d 2.49 (t, 1H), 3.77 (s, 3H), 4.22 (s, 2H), 4.32 (d, 2H).
Methyl (2-oxopropoxy)acetate (5). A solution of 4 (53 g, 0.40 mol) in
methanol (0.4 L) was treated with mercury(II) acetate (14 g, 0.04 mol), treated
with concentrated sulfuric acid (2 mL), refluxed for 20 minutes, cooled to
ambient temperature, concentrated under vacuum to a volume of 150 mL,
treated with 1 M HCl (150 mL) and extracted with dichloromethane
(5 Â 100 mL). The combined dichloromethane layers were dried (MgSO4),
filtered, concentrated and distilled (72–788C at 0.7–0.5 torr) to provide 33.3 g
(55 %) of 5: 1H NMR (CDCl3) d 2.18 (2, 3H), 3.77 (s, 3H), 4.20 (s, 2H), 4.21
(s, 2H).
Pyran-3,5-dione (6). A solution of 5 (50 g, 0.34 mol) in anhydrous ether
(1.0 L) was added dropwise over 2 hours to a mechanically stirred solution of
potassium tert-butoxide (1 M in tert-butanol, 340 mL) in anhydrous ether
(500 mL). The mixture was treated with 2 M HCl (200 mL) and the layers were

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Altenbach et al.
separated. The aqueous layer was extracted with ethyl acetate (2 Â 500 mL).
The combined organic layers were washed with brine (2 Â 100 mL), dried
(MgSO4), filtered and concentrated (keeping the water bath temperature below
308C). This crude product which crystallized on standing was treated with 1 : 1
hexane : ethyl acetate (200 mL). The crystals were collected by filtration,
washed with 1 : 1 hexane : ethyl acetate (100 mL) and dried under vacuum to
provide 12.2 g (31%) of 6: 1H NMR (DMSO-d6) d 4.07 (s, 4H), 5.32 (s, 1H),
11.9 (bs, 1H).
5-Amino-6H-pyran-3-one (1). A solution of compound 6 (0.5 g,
4.4 mmol) in ethanol (10 mL) was treated with conc. H2SO4 (5 drops), stirred
at ambient temperature over night, concentrated to a volume of approximately
3 mL, diluted with ether (50 mL), washed with saturated sodium bicarbonate
solution (15 mL), washed with brine, dried (MgSO4) and concentrated to
provide 0.52 g of the intermediate ethyl vinyl ether as a low melting point
white solid. This solid was treated with a solution of ammonia in ethanol
(10 mL), stirred over night at ambient temperature and concentrated to provide
0.38 g (77%) of 1 as a off white solid: MS (DCI/NH3) m/z 114 (M þ H)þ,
1
131 (M þ NH4)þ; H NMR (DMSO-d6) d 3.80 (s, 2H), 4.19 (s, 2H), 5.01 (s,
1H), 7.01 (bs, 2H). Anal. Calcd for C5H7NO2: C, 53.09; H, 6.24; N, 12.38.
Found: C, 53.20; H, 6.09; N, 12.25.
9-(3-Bromo-4-fluorophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]
thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide (12a). A mixture of compound
1 (1.5 g, 13 mmol), aldehyde 8 (3.2 g, 16 mmol), tetrahydrothiophene-3-oxo-
1,1-dioxide (10a)[10] (1.8 g, 13 mmol) and triethylamine (0.93 mL, 6.6 mmol)
in ethanol (20 mL) was stirred in a sealed tube at 808C for 60 hours, cooled and
concentrated to dryness. The residue was treated with ethanol (50 mL), treated
with 1 M HCl (in diethyl ether, 5 mL), heated to reflux for 5 minutes and kept
at ambient temperature for 3 hours. The resulting solid was collected by
filtration, washed with ethanol and dried under vacuum for 16 hours to provide
12a (3.2 g, 59 %): mp . 2608C; MS (ESI(þ)) m/z 414 (M þ H)þ, 431
1
(M þ NH4)þ; MS (ESI(2)) m/z 412 (M–H)2; H NMR (DMSO-d6) d 2.85
(m, 1H), 3.08 (m, 1H), 3.33–3.42 (m, 2H), 4.03 (s, 2H), 4.49 (AB q, 2H), 4.90
(s, 1H), 7.27 (m, 2H), 7.45 (dd, 1H), 10.14 (s, 1H); Anal. Calcd for
C16H13NO4SFBr: C, 46.39; H, 3.16; N, 3.38. Found: C, 46.25; H, 3.24;
N, 3.26.
General Example for Synthesis of Pyran Containing DHPs
5-(3-Bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b :
4,3-e]pyridine-4,6(7H,9H)-dione (3). A mixture of enaminone 1 (113 mg,
1.00 mmol), aldehyde 8 (255 mg, 1.25 mmol), compound 6 (114 mg,

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5-Amino-2H-pyran-3(6H)-one
563
1.0 mmol) and triethylamine (70 mL, 0.50 mmol) in ethanol (2 mL) was stirred
for 60 hours at 808C in a seated vessel and allowed to stand at ambient
temperature for 24 hours. The solid was collected by filtration, washed with
ethanol and dried under vacuum to provide 206 mg (52%) of 3: mp . 2508C;
MS (APCI(2)) m/z 392 (M–H)2; 1H NMR (DMSO-d6) d 4.06 (s, 4H), 4.41–
4.60 (AB qu, 4H), 4.94 (s, 1H), 7.19–7.32 (m, 2H), 7.42 (dd, 1H), 10.12 (br s,
.
1H); Anal. Calcd for C17H13BrFNO4 0.5 H2O: C, 50.64; H, 3.49; N, 3.47.
Found: C, 50.66; H, 3.56; N, 3.90.
10-(3-Bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H,5H-pyrano[3,4-
b]thiopyrano[2,3-e]pyridin-9(8H)-one 1,1-dioxide (12b). Substituting
10b[10] for 6 without triethylamine provided 12b (77%). MS (ESI(þ)) m/z
428 (M þ H)þ, 445 (M þ NH4)þ; MS (ESI(2)) m/z 426 (M–H)2; 1H NMR
(DMSO-d6) d 2.22 (m, 2H), 2.41–2.56 (m, 1H), 2.64 (dt, 1H), 3.09–3.35
(m, 2H), 4.02 (s, 2H), 4.43 (AB q, 2H), 5.06 (s, 1H), 7.25 (m, 2H), 7.41
(dd, 1H), 9.67 (bs, 1H); Anal. Calcd for C17H15NO4SFBr: C, 47.68; H, 3.53;
N, 3.27. Found: C, 47.36; H, 3.65; N, 3.06.
5-(3-Bromo-4-fluorophenyl)-5,7,8,9-tetrahydrocyclopenta[b]pyrano-
[4,3-e]pyridine-4,6(1H,3H)-dione (12c). Substituting 10c for 6 and sub-
stituting NH4OAc for Et3N provided 12c (32%): MS (ESI(þ)) m/z 378
1
(M þ H)þ, 395 (M þ NH4)þ; MS (ESI(2)) m/z 376 (M–H)2; H NMR
(DMSO-d6) d 2.31 (t, 2H), 2.59 (dt, 1H), 2.73 (dt, 1H), 4.04 (s, 2H), 4.53 (AB
q, 2H), 4.71 (s, 1H), 7.22 (m, 2H), 7.43 (dd, 1H), 10.36 (bs, 1H); Anal. Calcd
for C17H13NO3FBr: C, 53.99; H, 3.46; N, 3.70. Found: C, 53.68; H, 3.63; N,
3.63.
5-(3-Bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-pyrano[3,4-b]-
quinoline-4,6(3H,7H)-dione (12d). Substituting 10d for 6 provided 12d
(48%): MS (ESI(þ)) m/z 392 (M þ H)þ; MS (ESI(2)) m/z 390 (M–H)2;
1H NMR (DMSO-d6) d 1.76–2.01 (m, 2H), 2.25 (t, 2H), 2.43–2.64 (m, 2H),
4.01 (s, 2H), 4.48 (AB q, 2H), 4.90 (s, 1H), 7.20 (m, 2H), 7.39 (dd, 1H), 9.82
(bs, 1H); Anal. Calcd for C18H15HO3FBr: C, 55.12; H, 3.85; N, 3.57. Found:
C, 54.99; H, 4.04; N, 3.49.
10-(3-Bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b]-
[1,6]naphthyridine-1,9(5H,8H)-dione (12e). Substituting 10e[11] for 6
without Et3N provided 12e (52%): MS (APCI(þ)) m/z 393 (M þ H)þ; MS
1
(APCI(2)) m/z 391 (M–H)2; H NMR (DMSO-d6) d 2.38–2.60 (m, 2H),
3.18–3.26 (m, 2H), 4.00 (s, 2H), 4.45 (AB q, 2H), 4.95 (s, 1H), 7.14 (s, 1H),
7.16–7.28 (m, 2H), 7.41 (dd, 1H), 9.59 (s, 1H); Anal. Calcd for
C17H14N2O3FBr: C, 51.93; H, 3.59; N, 7.12. Found: C, 51.68; H, 3.83; N,
7.10.
8-Benzyl-5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-pyrano-
[3,4-b][1,7]naphthyridine-4,6(3H,7H)-dione (12f). Substituting 10f[5] for 6
provided, after concentration of the reaction mixture and chromatography of

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Altenbach et al.
the residue on silica gel using 5% MeOH in CH2Cl2, 12f (39%). MS (ESI(þ))
m/z 483 (M þ H)þ, 505 (M þ NH4)þ; MS (ESI(2)) m/z 481 (M–H)2;
1H NMR (CDCl3) d 3.06 (dd, 1H), 3.17 (d, 1H), 3.29 (d, 1 H), 3.39 (d, 1 H),
3.60 (d, 1 H), 3.68 (d, 1 H), 3.98 (d, 1 H), 4.13 (d, 1 H), 4.33 (AB q, 2 H), 5.09
(s, 1 H), 6.99 (t, 1 H) 7.26–7.37 (m, 6 H), 7.46 (dd, 1 H).
5-(3-Bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-pyrano[3,4-b]thio-
pyrano[4,3-e]pyridine-4,6(7H,9H)-dione (12g). Substituting 10g[12] for 6
provided 12g (39%): MS (ESI(þ)) m/z 410 (M þ H)þ, 427 (M þ NH4)þ; MS
1
(ESI(2)) m/z 408 (M–H)2; H NMR (DMSO-d6) d 3.12 (d, 1H), 3.50 (d,
2H), 3.81 (dd, 1H), 4.03 (s, 2H), 4.48 (AB q, 2H), 4.97 (s, 1H), 7.20 (ddd, 1H),
7.26 (t, 1H), 7.40 (dd, 1H), 9.98 (bs, 1H); Anal. Calcd for C17H13NO3SFBr: C,
49.77; H, 3.19; N, 3.41. Found: C, 49.43; H, 3.28; N, 3.21.
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