Strategy for the synthesis of 2,2-disubstituted 8-azachromanones via Horner–Wadsworth–Emmons olefination

Article abstract of DOI:10.1007/s10593-020-02646-z

[Figure not available: see fulltext.] A series of 2,2-disubstituted 8-azachromanones, including spirocyclic compounds, have been synthesized via Horner–Wadsworth– Emmons reaction. Dimethyl methylphosphonate was acylated with methyl 2-methoxypyridine-3-car

Full text of DOI:10.1007/s10593-020-02646-z

DOI 10.1007/s10593-020-02646-z
Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
Dedicated to Prof. V. P. Khilya on the occasion of his 81st birthday
Strategy for the synthesis of 2,2-disubstituted 8-azachromanones
via Horner–Wadsworth–Emmons olefination
1
,2
1,2
1,2
Taras V. Omelian , Eugeniy N. Ostapchuk , Alexey V. Dobrydnev ,
1,2
1
,3
3
Yehor S. Malets , Volodymyr S. Brovarets , Oleksandr O. Grygorenko *
1
Enamine Ltd.,
7
8 Chervonotkatska St., Kyiv 02094, Ukraine
2
3
Taras Shevchenko National University of Kyiv,
0 Volodymyrska St., Kyiv 01601, Ukraine; e-mail: gregor@univ.kiev.ua
6
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine,
1
Murmanska St., Kyiv 02094, Ukraine; e-mail: brovarets@bpci.kiev.ua
Published in Khimiya Geterotsiklicheskikh Soedinenii,
020, 56(2), 213–218
Submitted November 14, 2019
Accepted December 27, 2019
2
A series of 2,2-disubstituted 8-azachromanones, including spirocyclic compounds, have been synthesized via Horner–Wadsworth–
Emmons reaction. Dimethyl methylphosphonate was acylated with methyl 2-methoxypyridine-3-carboxylate to afford the key intermedi-
ate – dimethyl [2-(2-methoxypyridin-3-yl)-2-oxoethyl]phosphonate. Further reaction of this phosphonate and ketones followed by treatment with
TMSCl–NaI provided the target 8-azachromanones. Scope and limitations of the developed synthetic method have been investigated.
Keywords: azachromanone, phosphonate, cyclization, Horner–Wadsworth–Emmons reaction, olefination, protecting group.
Recently, 2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-one
(
8-azachromanone) scaffold has been in the spotlight of
medicinal chemistry as bioisosteric analog of chroman-
4
-one – a privileged structure in heterocyclic chemistry and
1
drug discovery. In this regard, 8-azachromanone is the key
structural motif of many biologically active compounds.
2
Among them, amlexanox (Fig. 1), which is the active
component of marketed drugs for treatment of aphthous
ulcers (canker sores), asthma, and allergic rhinitis that reduce
both healing time and pain, acts as anti-inflammatory and
antiallergic immunomodulator.3 In addition, amlexanox
was found to inhibit TANK-binding kinase 1 (TBK1) and
nuclear factor kappa-B kinase subunit e (IKKe) thus effectively
lowering the level of glycated hemoglobin (HbA1c).4
These results have promoted computational design of
amlexanox analogs for treatment of type 2 diabetes and
5
obesity. Finally, amlexanox binds to low molecular weight
2
+
6
Ca -binding proteins S100A12 and S100A13.
As other biologically active compounds, pyrido-
chromanones 1 and 2 (Fig. 1) have been identified as
Figure 1. Biologically active compounds containing 8-azachromanone
scaffold.
+
potent inhibitors of NAD -dependent DNA ligase from
0
009-3122/20/56(2)-0213©2020 Springer Science+Business Media, LLC
213

Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
7
E. coli. They also exhibit antibacterial activity against
pathogen S. aureus without affecting eukaryotic cells,
which is a prerequisite for the generation of a wide range of
according to the aforementioned strategy has been reported
in literature.19 This underlaid our attempts in investigation
of the substrate scope and limitations of the proposed
method. First of all, dimethyl [2-(2-methoxypyridin-3-yl)-
2-oxoethyl]phosphonate (5) was prepared in 88% yield by
LiHMDS-mediated condensation of methyl 2-methoxy-
pyridine-3-carboxylate (7) and dimethyl methylphospho-
nate (8) (Scheme 2).
8
specific antibacterial compounds. It has also been demon-
strated that 7-(phenylethynyl)-8-azachromanone (3) (Fig. 1)
acts as a positive allosteric modulator of metabotropic
9
glutamate receptor 5 (mGluR5). Such modulators are
interesting in terms of developing antipsychotics and
1
0
preventing the symptoms of schizophrenia.
Scheme 2
Several synthetic approaches for obtaining 2,2-disub-
stituted 8-azachromanones are known to date. For example,
condensation of 3-acetyl-2-pyridones and ketones (pathway
1
1
a), addition of vinyl Grignard reagents to 3-cyano-2-pyri-
1
1a,12
dones followed by acidic hydrolysis (pathway b),
acid-
and POCl -mediated cyclization of 3-(β-hydroxypropionyl)-
3
1
3
2
-methoxypyridines (pathway c), as well as multistep
14
transformations of 2H-pyrano[2,3-b]pyridines (pathway d)
NaH-promoted HWE reaction of β-ketophosphonate 5
and ketones or aldehydes 9a–j in THF provided a series of
α,β-unsaturated ketones 6a–j. The crude intermediates
were further subjected to treatment with TMSCl–NaI
followed by aqueous workup. The most suitable substrates
for the two-step reaction sequence described above were
ketones 9a–g with methylene groups at both sides of the
carbonyl group, as they provided the desired 8-azachromano-
nes 4a–g (Table 1, entries 1–7). However, 8-azachroma-
none 4b, derived from cyclobutanone (9b), was isolated in
have been reported (Scheme 1).
Scheme 1
Table 1. Synthesis of 8-azachromanones 4a–g*
Carbonyl
compound
R1/R2
Yield**,
%
Entry
Product
1
9a
9b
9c
9d
9e
9f
Me/Me
4a
4b
64
8
In the present work, we focused on development of an
alternative strategy for the synthesis of 2,2-disubstituted
2
(CH
(CH2)4
(CH
(CH O(CH
N(CO Et)(CH
N(Ms)(CH
2 3
)
3
4c
42
71
43
37
51
17
86
7
8
-azachromanones 4, which is based on Horner–Wadsworth–
4
2
)
5
4d
15
Emmons (HWE) reaction (Scheme 1). The notable
features of this chemical transformation that make it both
rational and general for obtaining compounds 4 from
dimethyl phosphonate 5 are application of inexpensive and
readily available starting materials, mild reaction condi-
tions, as well as formation of easily removable byproducts
5
2
)
2
2
)
2
4e
6
(CH
2
)
2
2
2
2
)
2
4f
7
8
9g
9h
9i
(CH
(CH
2
)
2
2
)
4g
2
)
2
N(Bn)(CH
H/Ph
2
)
2
10h·HI
10i
11
9
(
water-soluble phosphate salts). β-Ketophosphonates,
10
9j
3 5
H/cycloC H
necessary for the HWE reaction to afford α,β-unsaturated
ketones 6, can be easily produced from dialkyl methyl-
phosphonates via deprotonation with strong bases (e.g.,
11***
12***
9k
9l
Me/Ph
–
–
Me/i-Pr
–
–
*
Amounts of reactants and solvent, step 1: phosphonate 5 (1.05 g, 4 mmol),
16
17
18
n-BuLi, LDA, or LiHMDS ) at low temperature
carbonyl compound 9a–e,i,j (20 mmol) or 9f–h (8 mmol), NaH (60%
dispersion in mineral oil, 0.18 g, 4.4 mmol), THF (20 ml). Crude interme-
diates 6a–j were used in next step. Step 2: TMSCl (0.6 ml, 4.4 mmol), NaI
8c
(
usually –78°C)1
followed by treatment with the
corresponding esters, anhydrides, or acyl chlorides.
(
*
0.66 g, 4.4 mmol), MeCN (20 ml).
* Yield based on phosphonate 5.
*** After the first step, starting materials were recovered.
To the best of our knowledge, only synthesis of
1
2
2
,2-dimethyl-8-azachromanone (4a) (R = R = Me)
2
14

Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
low yield (8%) due to significant formation of tar (entry 2).
In summary, an efficient approach to gram-scale synthesis
of 2,2-disubstituted 8-azachromanones based on Horner–
Wadsworth–Emmons reaction of dimethyl [2-(2-methoxy-
pyridin-3-yl)-2-oxoethyl]phosphonate and carbo- or hetero-
cyclic ketones has been developed. It was found that
substrate scope of this method includes ketones with two
methylene groups adjacent to the carbonyl group.
Moreover, acid-labile functional groups as well as strongly
basic centers, for example, tertiary amines were not tolerated.
The developed procedure provides access to mono- and
Under the reaction conditions, sterically hindered aceto-
phenone (9k) and methyl isopropyl ketone (9l) failed to
produce the corresponding intermediates 6k,l (entries 11–12).
Both carbo- and heterocyclic ketones could be used as
starting materials leading to spirocyclic 8-azachromanone
derivatives 4b–g (entries 2–7). As it might be expected, the
protecting group of N-Boc-piperidone was incompatible
with the reaction conditions, while ethoxycarbonyl and
mesyl groups were tolerated (entries 6 and 7). Meanwhile,
benzyl protecting group was stable under the applied
conditions, but the corresponding intermediate 10h did not
undergo further cyclization (entry 8). Possibly, deactivating
effect of the protonated piperidine fragment might be
addressed to some conformational constraints introduced
by this moiety.
3
bifunctional sp -enriched natural product-like scaffolds,
which have a great potential for early drug discovery.
Experimental
1H and 13C spectra were obtained on a Varian Mercury
400 spectrometer (400 MHz (compounds 4a–f,m, 5, 10i)
and 100 MHz (compounds 4b,m, 10h·HI), respectively)
and a Bruker Avance 500 spectrometer (500 MHz
(compounds 4g, 10h·HI, 11) and 126 MHz (compounds
All attempts to exploit benzaldehyde (9i) as starting
material did not work even when the cyclization was
performed at elevated temperatures. Instead of product 4i,
either intermediate 6i or 2-pyridone derivative 10i was
isolated (Table 1, entry 9). Most likely, α,β-unsaturated
carbonyl moiety participates in conjugation with the benzene
ring thereby reducing its electrophilicity and precluding the
expected intramolecular cyclization. In the case of cyclo-
propanecarbaldehyde (9j), a complex mixture was obtained
upon treatment of intermediate 6j with TMSCl–NaI.
Chromatographic separation of this mixture allowed
isolating unusual side product 11 in 7% yield (entry 10,
Scheme 3) and recover ca. 20% of intermediate 6j.
4a,c–g, 5, 10i, 11), respectively) in DMSO-d
6
(compounds
4b,e,f,m, 10h·HI) or CDCl
3
(compounds 4a,c,d,g, 5, 10i,
31
11) using TMS as internal standard. P NMR spectrum of
compound 5 was obtained on a Bruker Avance 500
spectrometer (202 MHz) in CDCl
3
using H
3
PO as internal
4
standard. Mass spectra were recorded on Agilent 1100 LC/
MSD SL (APCI, compounds 4b–g, 10h·HI, 10i, 11) and
Agilent 5890 Series II 5972 GC/MS (EI, 70 eV, com-
pounds 4a, 5) instruments. HRMS analyses were conducted
on an Agilent 1260 Infinity UHPLC instrument coupled
with an Agilent 6224 Accurate Mass TOF mass spectro-
Scheme 3
meter. Elemental analyses were performed on
a
vario MICRO cube elemental analyzer. Melting points were
measured on an OptiMelt MPA100 automated melting
point apparatus. Progress of reactions was monitored by
TLC on Polychrom SI F254 plates using MTBE–MeOH,
1
:1, as eluent (visualization with UV light). Compound 4m
was purified by preparative HPLC on an Agilent 1260 Infinity
instrument, column Waters SunFire C18 (10 × 190 mm,
particle size 5 μm), gradient elution with H O–MeCN.
2
All starting materials were purchased from Enamine
Ltd. and UORSY. Solvents were purified according to
standard procedures.21
Formation of furan derivative 11 might be rationalized
via nucleophilic attack of iodide anion at the cyclopropane
moiety of compound 6j with simultaneous formation of
intermediate 12 containing silylated 4,5-dihydrofuran ring.
Upon workup procedure, the latter undergoes desilylation and
subsequent aromatization to afford compound 11 (Scheme 3).
To demonstrate the utility of the developed synthetic
method, N-mesyl-protected 8-azachromanone derivative 4g
was subjected to deprotection upon prolonged refluxing
with aq HCl to afford spirocyclic compound 4m, a
Dimethyl [2-(2-methoxypyridin-3-yl)-2-oxoethyl]-
phosphonate (5). Dimethyl methylphosphonate (8)
(12.4 g, 0.10 mol) was dissolved in THF (300 ml), and the
solution was cooled to –78°C. A 1 M solution of LiHMDS
in PhMe (110 ml, 0.11 mol) was added dropwise upon
stirring at –78°C, and the resulting mixture was stirred for
30 min. After warming to –60°C, a solution of methyl
2-methoxypyridine-3-carboxylate (7) (10.0 g, 0.06 mol) in
THF (60 ml) was added. The reaction mixture was stirred
at –60°C for 1 h, then allowed to warm to 0°C, quenched
3
promising sp -enriched bifunctional building block for
2
0
medicinal chemistry, in 70% yield (Scheme 4).
with saturated aq NH
CH Cl (3×300 ml). The combined organic layers were
dried over anhydrous Na SO . The crude product was
purified by column chromatography (SiO , eluent MTBE–
4
Cl (250 ml), and extracted with
Scheme 4
2
2
2
4
2
1
MeOH, 95:5). Yield 13.7 g (88%), yellow liquid. H NMR
spectrum, δ, ppm (J, Hz): 8.32 (1H, dd, J = 4.9, J = 2.1,
H-4); 8.10 (1H, dd, J = 7.6, J = 2.1, H-6); 6.99 (1H, dd,
2
15

Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
+
J = 7.6, J = 4.9, H-5); 4.07 (3H, s, OCH
3
); 3.85 (2H, d,
); 3.73 (3H, s, POCH ).
(Irel, %): 204 [M+H] (100). Found, %: C 70.64; H 6.10;
J = 21.8, CH
2
); 3.76 (3H, s, POCH
3
3
N 7.04. C12
H
13NO . Calculated, %: C 70.92; H 6.45; N 6.89.
2
1
3
C NMR spectrum, δ, ppm (J, Hz): 191.7 (d, J = 7.1);
61.8; 151.5; 140.4; 121.0 (d, J = 3.1); 117.3; 54.0; 52.9 (d,
Spiro[cyclohexane-1,2'-pyrano[2,3-b]pyridin]-4'(3'H)-
1
1
one (4d). Yield 0.62 g (71%), yellow oil. H NMR spectrum,
3
1
J = 6.4); 41.6; 40.6. P NMR spectrum, δ, ppm: 23.8. Mass
δ, ppm (J, Hz): 8.43 (1H, dd, J = 4.7, J = 2.1, H-7); 8.16
(1H, dd, J = 7.6, J = 2.1, H-5); 7.00 (1H, dd, J = 7.5,
+
+
spectrum, m/z (Irel, %): 259 [M] (3), 149 [M–PO(OMe)
2
]
+
(
25), 134 [M–Me–PO(OMe)
2
] (100). Found, %: C 46.11;
P. Calculated, %: C 46.34;
J = 4.8, H-6); 2.73 (2H, s, C(O)CH
CH ); 1.87–1.74 (2H, m, CH
1.26 (1H, m, 3CH
2
); 2.06–1.95 (2H, m,
H 5.11; N 5.14. C10
H
14NO
5
2
2
); 1.67–1.45 (5H, m) and 1.39–
13
H 5.44; N 5.40.
2
). C NMR spectrum, δ, ppm: 192.4;
Synthesis of pyrano[2,3-b]pyridin-4(3H)-ones 4a–g
164.4; 155.0; 136.3; 117.9; 115.3; 80.4; 47.6; 34.9; 25.0;
+
(
0
General method). NaH (60% dispersion in mineral oil,
21.3. Mass spectrum, m/z (Irel, %): 218 [M+H] (100).
.18 g, 4.4 mmol) was added under argon atmosphere at
Found, %: C 71.59; H 7.22; N 6.29. C13
Calculated, %: C 71.87; H 6.96; N 6.45.
H
15NO .
2
room temperature to a solution of phosphonate 5 (1.05 g,
.0 mmol) in THF (20 ml). The resulting mixture was
4
2,3,5,6-Tetrahydrospiro[pyran-4,2'-pyrano[2,3-b]-
pyridin]-4'(3'H)-one (4e). Yield 0.38 g (43%), yellow
stirred at room temperature for 30 min, then cooled in an
ice bath. Ketone 9a–e (20 mmol) or 9f,g (8 mmol) was
added, the mixture was allowed to warm to room tempe-
rature and then refluxed for 48 h. After cooling to room
temperature, the mixture was concentrated under reduced
1
crystals, mp 131–134°C. H NMR spectrum, δ, ppm (J, Hz):
8.49 (1H, dd, J = 4.8, J = 2.1, H-7); 8.14 (1H, dd, J = 7.6,
J = 2.1, H-5); 7.17 (1H, dd, J = 7.6, J = 4.8, H-6); 3.75–
3.59 (4H, m, 2OCH
1.71 (4H, m, 2OCH
2
CH
CH
2
); 2.93 (2H, s, C(O)CH ); 1.90–
2
2
13
pressure. The residue was diluted with H
extracted with EtOAc (3×25 ml). The combined extracts
were dried over anhydrous Na SO . The obtained crude
α,β-unsaturated ketone 6a–g was dissolved in MeCN
20 ml), and TMSCl (0.6 ml, 4.4 mmol) and NaI (0.66 g,
.4 mmol) were added at room temperature. The resulting
mixture was stirred at room temperature for 12 h, diluted
with H O (40 ml), and extracted with CH Cl (3×30 ml).
The combined organic layers were dried over anhydrous
Na SO . The crude product was purified by column
chromatoraphy (SiO , eluent MTBE–MeOH, 1:1).
,2-Dimethyl-2,3-dihydro-4H-pyrano[2,3-b]pyridin-
-one (4a). Yield 0.45 g (64%), beige crystals, mp 97–98°C.
2
O (20 ml) and
2
). C NMR spectrum, δ, ppm:
192.3; 164.0; 155.5; 136.4; 119.0; 115.4; 77.8; 62.8; 46.9; 34.7.
+
2
4
Mass spectrum, m/z (Irel, %): 220 [M+H] (100). Found, %:
C 65.81; H 5.74; N 6.63. C12
C 65.74; H 5.98; N 6.39.
H
13NO . Calculated, %:
3
(
4
Ethyl 4'-oxo-3',4'-dihydro-1H-spiro[piperidine-4,2'-
pyrano[2,3-b]pyridine]-1-carboxylate (4f). Yield 0.43 g
1
(37%), yellow oil. H NMR spectrum, δ, ppm (J, Hz): 8.45
2
2
2
(1H, dd, J = 4.9, J = 2.0, H-7); 8.10 (1H, dt, J = 7.5, J = 2.0,
H-5); 7.14 (1H, dd, J = 7.5, J = 4.9, H-6); 4.00 (2H, q, J = 7.2,
2
4
OCH
(2H, m, NCH
J = 13.4, NCH
NCH CH
2
CH
3
); 3.74 (2H, d, J = 13.4, NCH
2
CH
); 1.86 (2H, d,
); 1.66 (2H, td, J = 13.4, J = 4.6,
2
); 3.27–2.98
2
2
2
CH
2
2
); 2.88 (2H, s, C(O)CH
2
4
CH
2
1
13
H NMR spectrum, δ, ppm (J, Hz): 8.45 (1H, dd, J = 4.7,
2
2
); 1.13 (3H, t, J = 7.2, OCH
2
CH ). C NMR
3
J = 2.2, H-7); 8.19 (1H, dd, J = 7.5, J = 2.2, H-5); 7.02
spectrum, δ, ppm: 192.2; 163.9; 155.5; 155.0; 136.4; 119.0;
(
(
1H, dd, J = 7.5, J = 4.7, H-6); 2.76 (2H, s, C(O)CH
2
); 1.52
). C NMR spectrum, δ, ppm: 192.2; 164.6;
55.1; 136.4; 117.9; 114.7; 79.4; 48.4; 26.7. Mass
115.4; 78.4; 61.2; 46.6; 39.4; 33.7; 15.0. Mass spectrum,
13
+
6H, s, 2CH
3
m/z (Irel, %): 291 [M+H] (100). Found, %: C 62.25;
1
H 6.20; N 9.39. C15
H 6.25; N 9.65.
H
18
N
2
O . Calculated, %: C 62.06;
4
+
+
spectrum, m/z (Irel, %): 177 [M] (94), 162 [M–Me] (100),
+
1
21 [M–H
2
H
C=C(CH
3
)
2
] (66). Found, %: C 67.56; H 6.15;
1-(Methylsulfonyl)spiro[piperidine-4,2'-pyrano[2,3-b]-
pyridin]-4'(3'H)-one (4g). Yield 0.60 g (51%), white
N 8.08. C10
11NO
2
. Calculated, %: C 67.78; H 6.26; N 7.90.
1
Spiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'(3'H)-
one (4b). Yield 60 mg (8%), white crystals, mp 100–102°C.
crystals, mp 195–196°C. H NMR spectrum, δ, ppm (J, Hz):
8.47 (1H, d, J = 2.5, H-7); 8.22 (1H, dd, J = 7.6, J = 2.5,
H-5); 7.10 (1H, dd, J = 7.6, J = 4.8, H-6); 3.67 (2H, dt,
1
H NMR spectrum, δ, ppm (J, Hz): 8.48 (1H, dd, J = 4.6,
J = 2.1, H-7); 8.13 (1H, dd, J = 7.5, J = 2.1, H-5); 7.17
J = 12.0, J = 4.8, NCH
J = 2.5, NCH CH ); 2.80 (3H, s, SO
C(O)CH ); 2.17 (2H, d, J = 12.0, NCH
2
CH
2
); 3.20 (2H, td, J = 12.0,
CH ); 2.79 (2H, s,
CH ); 1.86 (2H, td,
13
(
1H, dd, J = 7.5, J = 4.6, H-6); 3.04 (2H, s, C(O)CH
2
); 2.35–
); 1.92–1.70
). C NMR spectrum, δ, ppm: 192.6; 164.3;
55.5; 136.6; 119.1; 115.5; 80.6; 45.1; 33.0; 12.1. Mass
2
2
2
3
2
.20 (2H, m, CH
2
); 2.20–2.05 (2H, m, CH
2
2
2
2
13
(
2H, m, CH
2
J = 12.0, J = 4.8, NCH
2
CH ). C NMR spectrum, δ, ppm:
2
1
190.7; 163.5; 155.1; 136.9; 118.8; 115.3; 77.1; 47.5; 41.2;
+
+
spectrum, m/z (Irel, %): 190 [M+H] (100). Found, %:
34.9; 34.1. Mass spectrum, m/z (Irel, %): 297 [M+H] (100).
C 69.53; H 5.52; N 7.67. C11
C 69.83; H 5.86; N 7.40.
H
11NO
2
. Calculated, %:
Found, %: C 52.55; H 5.64; N 9.15; S 10.90. C13
Calculated, %: C 52.69; H 5.44; N 9.45; S 10.82.
H
16
N
2
O S.
4
Spiro[cyclopentane-1,2'-pyrano[2,3-b]pyridin]-4'(3'H)-
1-Benzyl-4-[2-oxo-2-(2-oxo-1,2-dihydropyridin-3-yl)-
ethylidene]piperidinium iodide (10h·HI). Obtained from
ketone 9h (1.51 g, 8.0 mmol) according to general method
for the synthesis of compounds 4a–g. After extraction with
EtOAc (3×25 ml), the combined organic layers were
discarded and aqueous layer was allowed to stand at room
temperature for 12 h. The precipitate formed was filtered
off and air-dried. Yield 0.30 g (17%), white crystals,
1
one (4c). Yield 0.34 g (42%), yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 8.42 (1H, dd, J = 4.8, J = 2.2, H-7); 8.18
(
1H, dd, J = 7.6, J = 2.2, H-5); 7.01 (1H, dd, J = 7.6,
J = 4.8, H-6); 2.85 (2H, s, C(O)CH
2
); 2.18–2.07 (2H, m,
); 1.76–1.60 (4H, m, 2CH ).
CH ); 2.00–1.88 (2H, m, CH
2
2
2
1
3
C NMR spectrum, δ, ppm: 192.3; 165.1; 154.9; 136.6;
18.0; 115.4; 90.0; 46.5; 37.7; 23.8. Mass spectrum, m/z
1
2
16

Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
1
mp 217–218°C. H NMR spectrum, δ, ppm (J, Hz): 12.26
The work was funded by Enamine Ltd.
+
(
1H, s, C(O)NH); 9.87 (1H, s, NH(CH
2
)
3
); 8.05 (1H, d,
O. O. Grygorenko and A. V. Dobrydnev received additional
funding from Ministry of Education and Science of Ukraine
(grant 19BF037-03).
J = 7.2, H-4); 7.74 (1H, d, J = 6.5, H-6); 7.51 (2H, d,
J = 7.2, H-3,5 Ph); 7.46 (3H, d, J = 7.2, H-2,4,6 Ph); 6.35
(
1H, t, J = 6.5, H-5); 5.48 (1H, s, C(O)CH); 4.37 (2H, s,
The authors thank Prof. A. A. Tolmachev for his
encouragement and support, Mr. D. V. Bylina for HRMS
measurements, and reviewer for his help with elucidation
of the structure of compound 11.
NCH
2
Ph); 3.90–3.78 (2H, m) and 3.67–3.55 (2H, m,
NCH CH ); 3.48–3.40 (1H, m), 3.15–3.06 (1H, m), 2.47–
.36 (1H, m), and 2.31–2.22 (1H, m, 2NCH CH ). C NMR
2
2
2
2
13
2
2
spectrum, δ, ppm: 196.7; 161.5; 145.0; 142.6; 132.5; 131.7;
References
1
4
30.2; 130.1; 129.4; 126.6; 117.3; 105.7; 58.2; 49.6; 49.3;
+
1. (a) Malets, Y. S.; Moskvina, V. S.; Grygorenko, O. O.;
8.1; 25.8. Mass spectrum, m/z (Irel, %): 309 [M+H] (100).
Brovarets, V. S. Chem. Heterocycl. Compd. 2019, 55, 1007.
Found, %: C 52.38; H 4.96; N 6.54. C19
H
21IN
2
O .
2
[
Khim. Geterotsikl. Soedin. 2019, 55, 1007.] (b) Emami, S.;
Calculated, %: C 52.31; H 4.85; N 6.42.
Ghanbarimasir, Z. Eur. J. Med. Chem. 2015, 93, 539.
c) Durham, T. B.; Blanco, M.-J. Bioorg. Med. Chem. Lett.
015, 25, 998.
3
-[(2Z)-3-Phenylprop-2-enoyl]pyridin-2(1H)-one (10i).
(
2
Obtained from benzaldehyde (9i) (2.0 ml, 20.0 mmol).
Yield 0.77 g (86%), beige crystals, mp 172–174°C.
2. (a) Nohara, A.; Ishiguro, T.; Ukawa, K.; Sugihara, H.; Maki, Y.;
Sanno, Y. J. Med. Chem. 1985, 28, 559. (b) Vora, K. R.;
Khandwala, A.; Smith, C. G. US Patent 5362737.
1
H NMR spectrum, δ, ppm (J, Hz): 13.13 (1H, s, C(O)NH);
8
.26 (1H, dd, J = 7.2, J = 2.2, H-4); 7.98 (1H, d, J = 15.8,
3
. (a) Khandwala, A.; Van Inwegen, R. G.; Alfano, M. C. Oral
Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1997, 83,
222. (b) Bailey, J.; McCarthy, C.; Smith, R. F. J. Fam.
Practice 2011, 60, 621. (c) Burgess, J. A.; Van der Ven, P. F.;
Martin, M.; Sherman, J.; Haley, J. J. Contemp. Dent. Pract.
C(O)CH=CH); 7.81 (1H, d, J = 15.8, C(O)CH=CH); 7.73–
7
6
1
1
2
.56 (3H, m, H-6, H-2,6 Ph); 7.47–7.30 (3H, m, H-3,4,5 Ph);
13
.46 (1H, t, J = 6.7, H-5). C NMR spectrum, δ, ppm:
88.9; 163.7; 145.4; 143.5; 140.0; 135.2; 130.4; 128.9;
28.7; 128.3; 125.3; 107.3. Mass spectrum, m/z (Irel, %):
2
008, 9, 88. (d) Bell, J. Clin. Drug. Invest. 2005, 25, 555.
+
26 [M+H] (100). Found, %: C 74.89; H 4.63; N 6.16.
4. Oral, E. A.; Reilly, S. M.; Gomez, A. V.; Meral, R.; Butz, L.;
Ajluni, N.; Chenevert, T. L.; Korytnaya, E.; Neidert, A. H.;
Hench, R.; Rus, D.; Horowitz, J. F.; Poirier, B.; Zhao, P.;
Lehmann, K.; Jain, M.; Yu, R.; Liddle, C.; Ahmadian, M.;
Downes, M.; Evans, R. M.; Saltiel, A. R. Cell Metab. 2017,
26, 157.
C
14
3
H
11NO . Calculated, %: C 74.65; H 4.92; N 6.22.
2
-[5-(2-Iodoethyl)furan-2-yl]-2-methoxypyridine (11).
Obtained from cyclopropanecarbaldehyde (9j) (1.5 ml,
0.0 mmol). Yield 90 mg (7%), white solid, mp 134–136°C.
2
1
H NMR spectrum, δ, ppm (J, Hz): 8.05 (1H, dd, J = 4.9,
J = 1.5, H-6); 8.03 (1H, dd, J = 7.5, J = 1.5, H-4); 6.95
1H, dd, J = 7.5, J = 4.9, H-5); 6.92 (1H, d, J = 3.3, H-3');
.24 (1H, d, J = 3.3, H-4'); 4.07 (3H, s, OCH ); 3.40 (2H, t,
CH I).
5
. (a) Beyett, T. S.; Gan, X.; Reilly, S. M.; Gomez, A. V.;
Chang, L.; Tesmer, J. J. G.; Saltiel, A. R.; Showalter, H. D.
Bioorg. Med. Chem. 2018, 26, 5443. (b) Gan, X.; Wilson, M. W.;
Beyett, T. S.; Wen, B.; Sun, D.; Larsen, S. D.; Tesmer, J. J. G.;
Saltiel, A. R.; Showalter, H. D. J. Labelled Compd.
Radiopharm. 2019, 62, 202. (c) Beyett, T. S.; Gan, X.; Reilly, S. M.;
Chang, L.; Gomez, A. V.; Saltiel, A. R.; Showalter, H. D.;
Tesmer, J. J. G. Mol. Pharmacol. 2018, 94, 1210.
. Okada, M.; Tokumitsu, H.; Kubota, Y.; Kobayashi, R.
Biochem. Biophys. Res. Commun. 2002, 292, 1023.
. Brötz-Oesterhelt, H.; Knezevic, I.; Bartel, S.; Lampe, T.;
Warnecke-Eberz, U.; Ziegelbauer, K.; Häbich, D.;
Labischinski, H. J. Biol. Chem. 2003, 278, 39435.
. (a) Pankiewicz, K. W.; Chen, L.; Petrelli, R.; Felczak, K.;
Gao, G.; Bonnac, L.; Yu, J. S.; Bennett, E. M. Curr. Med.
Chem. 2008, 15, 650. (b) Dwivedi, N.; Dube, D.; Pandey, J.;
Singh, B.; Kukshal, V.; Ramachandran, R.; Tripathi, R. P.
Med. Res. Rev. 2008, 28, 545.
9. Varnes, J. G.; Marcus, A. P.; Mauger, R. C.; Throner, S. R.;
Hoesch, V.; King, M. M.; Wang, X.; Sygowski, L. A.; Spear, N.;
Gadient, R.; Brown, D. G.; Campbell, J. B. Bioorg. Med.
Chem. Lett. 2011, 21, 1402.
(
6
3
J = 7.5, CH
2
CH
2
I); 3.27 (2H, t, J = 7.5, CH
2
2
1
3
C NMR spectrum, δ, ppm: 158.9; 153.6; 147.8; 144.4; 133.0;
1
16.9; 114.6; 111.5; 108.9; 53.5; 32.8; 1.6. Mass spectrum,
+
+
m/z (Irel, %): 330 [M+H] (100), 188 [M–Me–I+H] (24).
6
Found, %: C 43.95; H 3.68; N 4.57. C12
H
12INO .
2
Calculated, %: C 43.79; H 3.68; N 4.26.
7
4
'-Oxo-3',4'-dihydrospiro[piperidinium-4,2'-pyrano-
[
2,3-b]pyridine] chloride (4m). A solution of 8-aza-
chromanone 4g (0.30 g, 1.0 mmol) in 20% aq HCl (6 ml)
was refluxed for 120 h. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by
preparative HPLC. The eluate was acidified with 20%
aq HCl to pH 3 and evaporated under reduced pressure.
8
1
Yield 0.18 g (70%), beige crystals, mp 212–215°C. H NMR
spectrum, δ, ppm (J, Hz): 9.45 (1H, s) and 9.26 (1H, s,
+
NH
2
(CH ) ); 8.51 (1H, d, J = 4.4, H-7); 8.17 (1H, d, J = 7.4,
2
2
H-5); 7.22 (1H, dd, J = 7.4, J = 4.5, H-6); 3.18 (2H, d,
J = 12.8, NCH CH ); 3.05 (2H, q, J = 11.4, NCH CH );
.98 (C(O)CH ); 2.12 (2H, d, J = 14.4, NCH CH ); 2.01
2H, t, J = 13.0, NCH ). C NMR spectrum, δ, ppm:
1
0. (a) Conn, J. P.; Tamminga, C.; Schoepp, D. D.; Lindsley, C.
Mol. Interventions 2008, 8, 99. (b) Lindsley, C. W.; Shipe, W. D.;
Wolkenberg, S. E.; Theberge, C. R.; Williams, D. L., Jr.; Sur, C.;
Kinney, G. G. Curr. Top. Med. Chem. 2006, 6, 771.
2
2
2
2
2
2
2
2
1
3
(
2
CH
2
(
c) Lindsley, C. W.; Emmitte, K. A. Curr. Opin. Drug
1
3
91.5; 163.4; 155.4; 136.8; 119.4; 115.4; 76.6; 46.2; 39.2;
+
Discovery Devel. 2009, 12, 446.
0.7. Found, m/z: 219.1129 [M+H] .
C
12
H
15
N
2
O .
2
1
1. (a) Madsen-Duggan, C. B.; Debenham, J. S.; Walsh, T. F.;
Yan, L.; Huo, P.; Wang, J.; Tong, X.; Lao, J.; Fong, T. M.;
Xiao, J. C.; Huang, C. R.; Shen, C.-P.; Stribling, D. S.;
Shearman, L. P.; Strack, A. M.; Goulet, M. T.; Hale, J. J.
Bioorg. Med. Chem. Lett. 2010, 20, 3750. (b) Lang, R. W.;
Wenk, P. F. Helv. Chim. Acta 1988, 71, 596.
Calculated, m/z: 219.1133.
Supplementary information file containing H and 13C
NMR spectra of the synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
1
2
17

Chemistry of Heterocyclic Compounds 2020, 56(2), 213–218
1
1
2. Yan, L.; Huo, P.; Debenham, J. S.; Madsen-Duggan, C. B.;
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Shearman, L. P.; Strack, A. M.; Tsou, N.; Ball, R. G.; Wang, J.;
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2
017, 27, 2594. (b) Cotterill, D. W.; Johnston, D. A.;
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1
1
19. Eastwood, P. R.; Gonzalez Rodriguez, J.; Gomez Castillo, E.;
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1
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2
18