Synthesis of 6-R-isoxazolo[4,3-b]pyridines and their reactions with C-nucleophiles

Article abstract of DOI:10.1007/s11172-020-2774-y

Available 2-chloro-3-nitropyridines were used to synthesize new representatives of 6-substituted 3-benzoylisoxazolo[4,3-b]pyridines, which were found to react with neutral C-nucleophiles to give 1,4-addition products.

Full text of DOI:10.1007/s11172-020-2774-y

394
Russian Chemical Bulletin, International Edition, Vol. 69, No. 2, pp. 394—397, February, 2020
Synthesis of 6-R-isoxazolo[4,3-b]pyridines and their reactions
with C-nucleophiles*
M. A. Bastrakov,a A. K. Fedorenko,a,b and A. M. Starosotnikovа
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: b_max82@mail.ru
b
Lomonosov Moscow State University, Department of Chemistry,
Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation
Available 2-chloro-3-nitropyridines were used to synthesize new representatives of 6-sub-
stituted 3-benzoylisoxazolo[4,3-b]pyridines, which were found to react with neutral C-nucleophiles
to give 1,4-addition products.
Key words: nitro group, nitropyridines, nucleophilic addition, dihydropyridines, dearoma-
tization.
Dihydropyridine derivatives are an important class of
react with neutral nucleophiles to form addition products,
1
6,17
organic compounds. The dihydropyridine ring is part of
a representative series of natural and synthetic compounds,
many of which exhibit biological activity.1 One of the
most popular methods for the synthesis of dihydropyridine
derivatives is the dearomatization of various functionalized
namely, derivatives of 1,4-dihydropyridine.
Isox-
azolo[4,3-b]pyridine derivatives С are among the available
bicycles closest to heterocyclic systems A and B in the
structure and electron-deficient character. In this con-
nection, the present work is devoted to the synthesis of
pyridine derivatives fused with the isoxazole ring and study
of their reactions with nucleophiles.
Available 2-chloro-3-nitropyridines 1a—d were used
as the starting compounds, which were introduced into
the cross-coupling reactions with phenylacetylene. The
cycloisomerization of compounds 2a—d in the presence
of catalytic amounts of ICl led to the target isoxazolo-
[4,3-b]pyridines 3a—d in good yields (Scheme 1).
,2
3
pyridines. Dearomatization as a synthetic method for
functionally complex saturated structures possesses an
enormous synthetic potential and consists in the transfor-
mation of available and simple aromatic compounds to
functionally complex, poorly available, and promising
intermediate products.3 Since the mid-1990s, the inter-
est in such processes and their synthetic application has
been steadily growing.
—9
The present work is a continuation of our research on
the application of the dearomatization strategy in the
Scheme 1
1
0—18
synthesis of new multifunctional azaheterocycles.
Earlier, we have shown that nitropyridines annulated with
π-deficient heterocycles (furoxan A and selenadiazole B)
R = Cl (a), H ( b), CO Me (c), NO (d)
2
2
*
Based on the materials of the International Markovnikov
Congress on Organic Chemistry (June 21—28, 2019, Moscow—
Kazan, Russia).
Reagents and conditions: i. Et N, THF, CuI, Pd(Ph ) Cl , 40 °C;
3 3 2 2
ii. CH Cl , Δ.
2
2
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0394—0397, February, 2020.
066-5285/20/6902-0394 © 2020 Springer Science+Business Media LLC
1

Nucleophilic addition to isoxazolopyridines
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
395
We studied the reactions of isoxazolopyridines 3a—d
with C-nucleophiles (dimedone and 1,3-dimethylbarbi-
turic acid). It was found that 6-chloroisoxazolo[4,3-b]-
pyridine (3a) does not give addition products even under
drastic conditions (80 °C). At the same time, 6-unsubsti-
tuted isoxazolopyridine 3b is capable of forming an adduct
with dimedone 4e (Scheme 2). However, unlike com-
pounds A and B, which react with dimedone within a few
minutes, a complete conversion of 3b requires 4 h. For
isoxazolopyridines 3c and 3d with electron-withdrawing
substituents at position 6, the reaction proceeded much
easier (less than within 1 h) resulting in good yields of
dihydroisoxazolopyridines 4a—e.
to react with neutral C-nucleophiles without assistance
with a base or a catalyst. The reaction is accompanied
by dearomatization of the pyridine ring to give 1,4-ad-
dition products.
Experimental
Melting points were measured on a Stuart SMP20 apparatus.
1
13
1
H and C NMR spectra were recorded on Bruker AM-300 ( H,
1
3
1
300 MHz; C, 75 MHz), Bruker Avance DRX 500 ( H,
1
3
500 MHz; C, 125 MHz), Bruker Avance II 600 instruments
1
13
( H, 600 MHz; C, 150 MHz). All the experiments were per-
formed according to standard Bruker procedures. Chemical shifts
are given relative to Me Si. Samples for NMR spectroscopy were
prepared in DMSO-d or CDCl . High resolution mass spectra
4
6
3
Scheme 2
(HRMS) were recorded on a Bruker maXis instrument using
electrospray ionization (ESI). The measurements were performed
in the positive ion mode (capillary voltage 4500 V). The mass
scan range at m/z 50—3000 Da, an external calibration with
Electrospray Calibrant Solution (Fluka). Solutions of compounds
–
1
in acetonitrile were syringed at the flow rate of 3 μL min . The
–
1
nebulizer gas nitrogen (4 L min ), the interface temperature
80 °C. Reaction progress and purity of compounds were
1
monitored by TLC on Silica gel 60 F254 plates (Merk). Com-
pounds 1a—d are commercially available (ABCR catalog).
Compounds 2b and 3b were synthesized according to the de-
1
9
scribed procedure.
Synthesis of compounds 2a—d (general procedure). A mixture
of the corresponding chloride 1 (5 mmol), PdCl (PPh ) (0.175 g,
2
3 2
0
.25 mmol), and Et N (1.4 mL, 10 mmol) was suspended in
3
anhydrous THF (20 mL). Then phenylacetylene (0.66 mL,
mmol) and CuI (0.025 g, 0.13 mmol) were added under argon.
The reaction mixture was stirred in an argon atmosphere for
—4 h at 40 °C (the reaction completion was detected by TLC).
Then the solvent was evaporated under reduced pressure. The
6
2
residue was purified by column chromatography (SiO —CHCl ).
2
3
5
-Chloro-3-nitro-2-(phenylethynyl)pyridine (2a). The yield
1
was 0.52 g (40%). M.p. 103—105 °C. H NMR (CDCl ), δ:
3
7
8
.41—7.48 (m, 3 H, Ph); 7.69—7.71 (d, 2 Н, Ph, J = 6.8 Hz);
4
a
b
c
R
NO2
NO2
Yield (%)
4
d
e
R
Me(O)OC
H
Yield (%)
75
.41 (d, 1 H, С(4)H, J = 1.6 Hz); 8,81 (d, 1 H, C(6)H, J = 1.6 Hz).
79
85
87
1
3
C NMR (CDCl ), δ: 84.3, 99.1, 121.2, 128.6, 130.3, 130.8,
70
3
Me(O)OC
132.2, 132.6, 135.4, 142.0, 145.7, 146.4, 152.6. HRMS (ESI):
+
found m/z 259.0259; calculated for С13Н ClN O [M + H]
7
2
2
2
59.0269.
3
The structure of the synthesized compounds was es-
tablished based on the NMR spectroscopy and high reso-
-Nitro-2-(phenylethynyl)pyridine (2b). The yield was 0.92 g
1
(
(
8
82%). M.p. 107—109 °C (see Ref. 24: 107—109 °C). H NMR
1
lution mass spectrometry data. The H NMR spectra of
CDCl ), δ: 7.42—7.51 (m, 4 H, ArH); 7.70—7.73 (m, 2 Н, ArH);
3
adducts 4a—e exhibit signals corresponding to the H(7)
protons in the region of δ 5.0—5.5, as well as low-field
doublets for the NH (δ 9.8—10.4) and H(5) protons (δ 8.1)
with close spin-spin coupling constants, which confirms
the addition of the nucleophile at position 7. This is con-
.42 (dd, 1 H, С(4)H, J = 8.1 Hz, J = 1.2 Hz); 8.84 (d, 1 H,
C(6)H, J = 3.6 Hz).
Methyl 5-nitro-6-(phenylethynyl)nicotinate (2c). The yield
1
was 1.07 g (76%). M.p. 117—119 °C. H NMR (CDCl3), δ: 4.05
(
s, 3 Н, Ме); 7.42—7.52 (m, 3 H, Ph); 7.71—7.74 (d, 2 Н, Ph,
J = 7.2 Hz); 8.95 (d, 1 H, С(4)H, J = 1.3 Hz); 9.39 (d, 1 H, C(6)
sistent with the results obtained earlier for the adducts with
1
3
other azolopyridines.16,17
H, J = 1.3 Hz). C NMR (CDCl3), δ: 53.9, 86.0, 102.0, 121.6,
1
25.6, 129.4, 131.4, 133.6, 134.1, 141.1, 147.1, 154.5, 164.1.
In conclusion, a series of new 6-substituted 3-benzo-
ylisoxazolo[4,3-b]pyridines were synthesized based on
the Sonogashira reaction of phenylacetylene with
HRMS (ESI): found m/z 283.0721; calculated for С15Н10N O
2
4
+
[
M + H] 283.0713.
3
,5-Dinitro-2-(phenylethynyl)pyridine (2d). The yield was
1
2
-chloro-3-nitropyridines and subsequent cycloiso-
0.97 g (72%). M.p. 183—185 °C. H NMR (CDCl ), δ: 7.45—7.54
3
merization. 6-R-Isoxazolo[4,3-b]pyridines were found
(m, 3 H, Ph); 7.74—7.76 (d, 2 Н, Ph, J = 7.2 Hz); 9.17 (s, 1 H,

3
96
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
Bastrakov et al.
С(4)H); 9.63 (s, 1 H, C(6)H). 13C NMR (DMSO-d ), δ: 64.0,
5.0, 100.8, 119.8, 128.7, 129.2, 131.3, 132.4, 142.3, 146.2, 148.3.
HRMS (ESI): found m/z 270.0514; calculated for С Н N O
4
δ: 3.04 (s, 3 Н, Ме); 3.17 (s, 3 Н, Ме); 4.65 (s, 1 Н, СН); 5.52
6
8
(s, 1 Н, Н(7)); 7.64 (t, 2 Н, Ph, J = 7.2 Hz); 7.75 (d, 1 Н, Ph,
J = 6.8 Hz); 8.13 (d, 3 Н, Ph and Н(5) , J = 7.1 Hz); 10.93
1
3
7
3
+
13
[
M + H] 270.0509.
(d, 1 Н, NH, J = 3.7 Hz). C NMR (DMSO-d ), δ: 28.6, 28.8,
6
Synthesis of compounds 3a—d (general procedure). The rea-
34.2, 34.3, 52.9, 123.6, 124.6, 129.5, 129.9, 134.9, 140.2, 151.6,
156.8, 166.7, 167.0, 167.1, 169.9, 171.8, 181.1. HRMS (ESI):
found m/z 426.1037; calculated for С19Н15N O [M + H]+
gent ICl (16 mg, 0.1 mmol) was added to a solution of the cor-
responding acetylene 2 (2 mmol) in CH Cl (20 mL). The reaction
2
2
5
7
mixture was refluxed with stirring for 4—8 h (TLC monitoring).
426.1044.
Then, the solvent was evaporated under reduced pressure. The
Methyl 3-benzoyl-7-(4,4-dimethyl-2,6-dioxocyclohexyl)-4,7-
dihydroisoxazolo[4,3-b]pyridin-6-carboxylate (4c). The yield was
residue was purified by column chromatography (SiO —CH Cl ).
2
2
2
1
6
-Chloroisoxazolo[4,3-b]pyridin-3-yl(phenyl)methanone (3a).
0.37 g (87%). M.p. 232—234 °C. H NMR (DMSO-d ), δ: 0.93
6
1
The yield was 0.31 g (60%). M.p. 120—122 °C. H NMR
(s, 6 H, 2 Ме); 2.16 (br.s, 4 Н, 2 СН ); 3.53 (s, 3 Н, СО Ме);
2
2
(
CDCl ), δ: 7.61 (t, 2 H, Ph, J = 7.6 Hz); 7.74 (t, 1 Н, Ph,
5.36 (s, 1 Н, Н(7)); 7.33 (s, 1 Н, Н(5)); 7.61 (t, 2 Н, Ph, J = 7.3 Hz);
3
J = 7.4 Hz); 8.14 (d, 1 H, С(4)H, J = 1.7 Hz); 8.23 (d, 2 Н, Ph,
7.70 (d, 1 Н, Ph, J = 7 Hz); 8.11 (d, 2 H, Ph, J = 7.6 Hz); 9.73
1
3
13
J = 7.5 Hz); 8.71 (s, 1 H, C(6)H). C NMR (CDCl ), δ: 121.6,
(d, NН, J = 5 Hz). C NMR (DMSO-d ), δ: 26.0, 27.1, 28.0,
3
6
1
1
28.3, 128.8, 130.3, 130.4, 131.8, 133.6, 134.5, 135.5, 151.3,
31.7, 50.7, 102.6, 128.7, 128.8, 129.0, 133.7, 135.6, 136.6, 136.7,
55.3, 161.0, 180.7. HRMS (ESI): found m/z 259.0276; calcu-
144.5, 157.4, 166.3, 180.4. HRMS (ESI): found m/z 423.1545;
+
+
lated for С13Н ClN O [M + H] 259.0269.
calculated for С23Н22N O [M + H] 423.1551.
7
2
2
2
6
Isoxazolo[4,3-b]pyridin-3-yl(phenyl)methanone (3b). The
Methyl 3-benzoyl-7-(1,3-dimethyl-2,4,6-trioxahexahydro-
yield was 0.36 g (80%). M.p. 95—96 °C (see Ref. 24: 95—96 °C).
pyrimidin-5-yl)-4,7-dihydroisoxazolo[4,3-b]pyridin-6-carboxyl-
1
1
H NMR (CDCl ), δ: 7.37 (dd, 1 H, C(6)H, J = 9.2 Hz, J = 3.6 Hz);
ate (4d). The yield was 0.33 g (75%). M.p. 170—172 °C. H NMR
3
7
8
.54—7.59 (m, 2 Н, ArH); 7.66—7.71 (m, 1 Н, С(4)Н);
(DMSO-d ), δ: 3.03 (s, 3 Н, Me); 3.13 (s, 3 H, Me); 3.63 (s, 3 H,
6
.20—8.23 (m, 2 Н, ArH); 8.84 (dd, 1 H, С(5)H, J = 3.6 Hz,
CO Me); 4.43 (s, 1 H, CH); 5.07 (s, 1 H, H(7)); 7.44 (d, 1 Н,
2
J = 1.5 Hz).
Н(5), J = 5.4 Hz); 7.63 (t, 2 Н, Ph, J = 7.3 Hz); 7.74 (t, 1 Н,
Methyl 3-benzoylisoxazolo[4,3-b]pyridin-6-carboxylate (3c).
Ph, J = 7.0 Hz); 8.12 (d, 2 Н, Ph, J = 7.7 Hz); 10.2 (d, 1 Н, NH,
1
13
The yield was 0.37 g (65%). M.p. 114—116 °C. H NMR
J = 5.3 Hz). C NMR (DMSO-d ), δ: 28.5, 28.6, 33.7, 51.8,
6
(
CDCl ), δ: 4.07 (s, 3 Н, Ме); 7.61 (t, 2 H, Ph, J = 7.6 Hz);
54.5, 99.6, 127.7, 129.5, 129.7, 134.5, 135.7, 139.4, 151.8, 166.8,
3
7
.74 (t, 1 Н, Ph, J = 7.4 Hz); 8.25 (d, 2 Н, Ph, J = 7.5 Hz); 8.85
167.3, 181.0. HRMS (ESI): found m/z 439.1242; calculated for
+
(
d, 1 H, С(4)H, J = 1.7 Hz); 9.36 (d, 1 H, C(6)H, J = 1.7 Hz).
С21Н18N O [M + H] 439.1248.
4
7
1
3
C NMR (CDCl ), δ: 53.2, 127.5, 127.7, 128.8, 130.5, 134.4,
2-(Benzoyl-4,7-dihydroisoxazolo[4,3-b]pyridin-7-yl)-5,5-
3
1
34.5, 135.6, 150.7, 154.9, 161.3, 164.1, 180.8. HRMS (ESI);
dimethylcyclohexane-1,3-dione (4e). The yield was 0.25 g (70%).
+
1
found m/z 283.0709; calculated for С15Н10N O [M + H]
M.p. 180—182 °C. H NMR (DMSO-d ), δ: 0.91 (s, 3 Н, Ме);
2
4
6
2
83.0713.
0.99 (s, 3 Н, Ме); 2.08—2.40 (m, 4 Н, 2 СН ); 4.33 (s, 1 Н,
2
6
-Nitroisoxazolo[4,3-b]pyridin-3-yl(phenyl)methanone (3d).
СН); 5.76 (s, 1 Н, Н(7)); 7.59—7.68 (m, 4 Н, Ph and С(5)Н);
1
13
The yield was 0.46 g (85%). M.p. 135—137 °C. H NMR
8.07—8.09 (d, 2 Н, Ph, J = 6.4 Hz); 8.45 (s, 1 Н, Н(5)). C NMR
(
CDCl ), δ: 7.63 (t, 2 H, Ph, J = 7.7); 7.77 (t, 1 Н, Ph, J = 7.4);
(DMSO-d ), δ: 19.4, 24.6, 27.0, 28.5, 31.9, 41.3, 49.7, 77.0,
3
6
8
9
1
1
.23 (d, 2 Н, Ph, J = 7.4 Hz); 9.08 (d, 1 H, С(4)H, J = 2.2 Hz);
110.4, 124.2, 126.8, 128.7, 128.8, 128.9, 130.3, 133.2, 134.4,
1
3
.55 (d, 1 H, C(6)H, J = 2.2 Hz). C NMR (CDCl ), δ: 122.7,
156.5, 169.5, 180.0, 194.2. HRMS (ESI): found 365.1494; cal-
3
+
29.7, 131.2, 134.9, 135.7, 135.9, 144.7, 149.6, 150.4, 163.0,
culated for С21Н20N O [M + H] 365.1496.
2
4
81.1. HRMS (ESI): found m/z 270.0508; calculated for
+
С13Н N O [M + H] 270.0509.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 17-03-
7
3
4
Synthesis of compounds 4a—e (general procedure). A cor-
responding СН-acid (1 mmol) was added to a solution of isoxa-
0
0809_а).
zole 3 (1 mmol) in anhydrous CH CN (5 mL). The reaction
3
mixture was stirred at room temperature for 1—4 h (TLC
monitoring). After completion of the reaction, the solution was
poured into water (25 mL), the precipitate formed was collected
by filtration and dried in air.
References
1. V. K. Sharma, S. K. Singh, RSC Adv., 2017, 7, 2682.
2. E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257.
3. G. Bertuzzi, L. Bernardi, M. Fochi, Catalysts, 2018, 8, 632.
4. G. Ramachandran, K. I. Sathiyanarayanan, Curr. Organocatal.,
2015, 2, 14.
5. A. S. Dudnik, V. L. Weidner, A. Motta, M. Delferro, T. Marks,
J. Nat. Chem., 2014, 6, 1100.
6. S. P. Roche, Jr., J. A. Porco, Angew. Chem., Int. Ed., 2011,
50, 4068.
7. P. L. Smith, M. D. Chordia, W. D. Harman, Tetrahedron,
2001, 57, 8203.
8. W. C. Wertjes, E. H. Southgate, D. Sarlah, Chem. Soc. Rev.,
2018, 47, 7996.
2
-(Benzoyl-6-nitro-4,7-dihydroisoxazolo[4,3-b]pyridin-7-
yl)-5,5-dimethylcyclohexane-1,3-dione (4a). The yield was 0.29 g
1
(
2
79%). M.p. 244—246 °C. H NMR (DMSO-d ), δ: 0.93 (s, 6 H,
6
Me); 2.25 (br.s, 5 Н, 2 СН ); 5.75 (br.s, 1 Н, Н(7)); 7.64 (t, 2 Н,
2
Ph, J = 7.5 Hz); 7.75 (t, 1 Н, Ph, J = 7.3 Hz); 8.01 (d, 1 Н, Н(5),
J = 5.7 Hz); 8.13 (d, 2 Н, Ph, J = 7.7 Hz); 10.55 (d, NН,
J = 6.1 Hz). 13C NMR (DMSO-d ), δ: 28.5, 29.5, 33.0, 43.7,
6
5
1.0, 127.9, 130.2, 130.5, 135.3, 136.3, 138.7, 147.5, 158.6, 181.9.
HRMS (ESI): found m/z 410.1340; calculated for С21Н19N O
3
6
+
[
M + H] 410.1347.
5
-(3-Benzoyl-6-nitro-4,7-dihydroisoxazolo[4,3-b]pyridin-
7
-yl)-1,3-dimethylpyrimidine-2,4,6(1Н,3Н,5Н)-trione (4b). The
1
yield was 0.36 g (85%). M.p. 234—235 °C. H NMR (DMSO-d ),
6

Nucleophilic addition to isoxazolopyridines
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
397
9
. V. N. Charushin, O. N. Chupakhin, Russ. Chem. Bull., 2019,
8, 453.
15. M. A. Bastrakov, A. Yu. Kucherova, A. K. Fedorenko, A. M.
Starosotnikov, I. V. Fedyanin, I. L. Dalinger, S. A. Shevelev,
Arkivoc, 2017, iii, 181.
16. A. M. Starosotnikov, D. V. Shkaev, M. A. Bastrakov, I. V.
Fedyanin, S. A. Shevelev, I. L. Dalinger, Beilstein J. Org.
Chem., 2017, 13, 2854.
6
1
0. L. S. Konstantinova, M. A. Bastrakov, A. M. Starosotnikov,
I. V. Glukhov, K. A. Lysov, O. A. Rakitin, S. A. Shevelev,
Mendeleev Commun., 2010, 20, 353.
1
1. M. A. Bastrakov, A. I. Leonov, A. M. Starosotnikov,
I. V. Fedyanin, S. A. Shevelev, Russ. Chem. Bull., 2013,
17. A. M. Starosotnikov, D. V. Shkaev, M. A. Bastrakov, S. A.
Shevelev, I. L. Dalinger, Mendeleev Commun., 2018, 28, 638.
18. M. A. Bastrakov, A. K. Fedorenko, A. M. Starosotnikov,
V. V. Kachala, S. A. Shevelev, Chem. Heterocycl. Compd.,
2019, 55, 72.
6
2, 1052.
1
2. M. A. Bastrakov, A. M. Starosotnikov, I. V. Fedyanin, V. V.
Kachala, S. A. Shevelev, Mendeleev Commun., 2014, 24, 203.
1
3. M. A. Bastrakov, A. M. Starosotnikov, A. A. Pavlov, I. L.
Dalinger, S. A. Shevelev, Chem. Heterocycl. Compd., 2016,
19. I. Cikotiene, Eur. J. Org. Chem., 2012, 2766.
5
2, 690.
1
4. A. M. Starosotnikov, M. A. Bastrakov, A. A. Pavlov, I. V.
Fedyanin, I. L. Dalinger, S. A. Shevelev, Mendeleev Commun.,
016, 26, 217.
Received October 1, 2019;
in revised form November 29, 2019;
accepted December 5, 2019
2