Synthesis of 1-Alkoxy-4-amino-3,6-dioxo-1-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles

Article abstract of DOI:10.1134/S1070428020060226

Abstract: 1-Alkoxy-4-amino-3,6-dioxo-1-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles have been synthesized with high yields byreaction of 4-amino-1-hydroxy-3,6-dioxo-1-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitril

Full text of DOI:10.1134/S1070428020060226

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 1112–1114. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 6, pp. 971–974.
SHORT
COMMUNICATIONS
Synthesis of 1-Alkoxy-4-amino-3,6-dioxo-1-phenyl-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles
Ya. S. Kayukova,*, A. A. Grigor’eva, S. V. Karpova, and O. V. Kayukovab,**
a I.N. Ul’yanov Chuvash State University, Cheboksary, 428015 Russia
b Chuvash State Agricultural Academy, Cheboksary, 428003 Russia
e-mail: *kaukovyakov@mail.ru; **olgakajukova@mail.ru
Received March 8, 2020; revised March 11, 2020; accepted March 16, 2020
Abstract—1-Alkoxy-4-amino-3,6-dioxo-1-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbo-
nitriles have been synthesized with high yields by reaction of 4-amino-1-hydroxy-3,6-dioxo-1-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile with the corresponding alcohols in the presence of
p-toluenesulfonic acid.
Keywords: pyridine, alcohol, pyrrolo[3,4-c]pyridine, hemiaminal
DOI: 10.1134/S1070428020060226
Derivatives of isoindolin-3-one and 5-azaisoindolin-
3-one exhibit various biological activities and are
therefore studied as drug candidates. For example,
inhibitors of SYK (antitumor activity) [1], MDM2
(apoptotic activity) [2], and InhA (antitubercular ac-
tivity) [3] have been found among these series of com-
pounds. We previously showed that sodium tetracyano-
propenides 1 are convenient precursors to polyfunction-
alized pyrrolo[3,4-c]pyridines possessing a hemiaminal
fragment [4–6]. With the aim of further modifying the
latter, we examined the possibility of replacing the
hemiaminal hydroxy group by alkoxy. This replace-
ment may be useful to enhance their lipophilicity.
According to published data, dehydroxylation/alkox-
ylation of such systems was accomplished using I2 [7],
SOCl2 [3], MsCl in the presence of triethylamie [8],
HCl [9], and camphorsulfonic acid [10]. We used as
starting compound 4-amino-1-hydroxy-3,6-dioxo-1-
phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-
7-carbonitrile (2) which was synthesized by treatment
of 1 with sodium hydroxide [4]. Compound 2 was
reacted with alcohols in the presence of sulfuric acid or
p-toluenesulfonic acid; the alcohol simultaneously
acted as a solvent. When an equimolar amount of the
acid was used, the reactions under reflux conditions
were complete in 0.5–1 h. 1-Alkoxy-4-amino-3,6-di-
oxo-1-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyr-
idine-7-carbonitriles 3a–3f were isolated in 53–77%
yield (Scheme 1), and their structure was confirmed by
IR, 1H and 13C NMR, and mass spectra.
4-Amino-1-methoxy-3,6-dioxo-1-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carboni-
trile (3a). A mixture of 0.564 g (0.002 mol) of com-
pound 2, 5 mL of methanol, and 0.034 g (0.0002 mol)
of p-toluenesulfonic acid was refluxed until the reac-
tion was complete (TLC, AcOEt–EtOH 9:1). The sol-
vent was distilled off, and the residue was crystallized
Scheme 1.
CN
CN
Ph
Ph
OH
NH
OR
NH
Ph
O
(1) NaOH, H2O, 50°C, 15 min
(2) H2SO4
ROH, TsOH
reflux, 0.5–1 h
O
O
NC
CN Na+
HN
HN
CN
CN
O
O
NH2
NH2
1
2
3a–3f
R=Me (a), Et (b), Pr (c), i-Pr (d), Bu (e), i-Bu (f).
1112

SYNTHESIS OF 1-ALKOXY-4-AMINO-3,6-DIOXO-1-PHENYL-...
1113
3
from aqueous acetonitrile. Yield 0.456 g (77%), white
powder, mp 207–209°C (decomp.). IR spectrum, ν,
cm–1: 3401, 3301, 3182, 3164 (NH, NH2), 2222 (C≡N),
1H NMR spectrum, δ, ppm: 1.18 d (3H, CH3, J =
3
6.1 Hz), 1.22 d (3H, CH3, J = 5.8 Hz), 3.67–3.75 m
(1H, OCH2), 7.32–7.65 m (7H, Harom, NH2), 8.93 s
(1H, N2H), 11.50 br.s (1H, N5H). 13C NMR spectrum,
δC, ppm: 23.9 (CH), 25.1 (CH), 62.5 (CH), 62.4 (CH),
67.0 (CH), 80.9, 91.0, 93.6, 115.2, 126.6 (CH), 128.5
(CH), 129.0, 139.3, 151.5, 162.3, 166.3, 167.3. Mass
spectrum, m/z (Irel, %): 324 (8.4) [M]+, 265 (100)
[M – OC3H7]+, 248 (19.7), 205 (16.4), 105 (24.2), 77
(48.8). Found, %: C 62.93; H 4.98; N 17.24.
C17H16N4O3. Calculated, %: C 62.95; H 4.97; N 17.27.
M 324.12.
1
1692, 1638 (C=O). H NMR spectrum, δ, ppm: 3.22 s
(3H, CH3), 7.30–7.70 m (7H, Harom, NH2), 8.83 s (1H,
N2H), 11.49 br.s (1H, N5H). 13C NMR spectrum, δC,
ppm: 50.6 (CH), 80.7, 91.6, 93.6, 114.9, 126.6 (CH),
128.6 (CH), 129.1, 138.5, 151.8, 162.2, 165.1, 167.6.
Mass spectrum, m/z (Irel, %): 296 (12) [M]+, 265 (48)
[M – OCH3]+, 248 (17), 187 (17), 57 (100). Found, %:
C 60.87; H 4.06; N 18.86. C15H12N4O3. Calculated, %:
C 60.81; H 4.08; N 18.91. M 296.09.
4-Amino-1-butoxy-3,6-dioxo-1-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carboni-
trile (3e). Yield 0.453 g (67%), white powder, mp 197–
199°C (decomp.). IR spectrum, ν, cm–1: 3407, 3279,
3244 (NH, NH2), 2219 (C≡N), 1709, 1675 (C=O).
Compounds 3b–3f were synthesized in a similar
way using the corresponding alcohol.
4-Amino-1-ethoxy-3,6-dioxo-1-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carboni-
trile (3b). Yield 0.347 g (56%), white powder,
mp 199–201°C (decomp.). IR spectrum, ν, cm–1: 3439,
3381, 3207, 3198 (NH, NH2), 2220 (C≡N), 1704, 1614
3
1H NMR spectrum, δ, ppm: 0.91 t (3H, CH3, J =
7.3 Hz), 1.45 non (2H, CH2, 3J = 7.3 Hz), 1.56–1.65 m
(2H, CH2), 3.16–3.24 m (1H, OCH2), 3.48–3.55 m
(1H, OCH2), 7.30–7.60 m (7H, Harom, NH2), 8.84 s
(1H, N2H), 11.48 br.s (1H, N5H). 13C NMR spectrum,
δC, ppm: 14.2 (CH), 19.4 (CH), 31.8 (CH), 62.4 (CH),
80.7, 91.0, 93.4, 114.8, 126.6 (CH), 128.6 (CH), 129.1,
138.8, 151.7, 162.2, 165.7, 167.5. Mass spectrum, m/z
(Irel, %): 338 (7) [M]+, 265 (91) [M – OC4H9]+, 248
(26), 105 (23), 57 (100). Found, %: C 63.93; H 5.37;
N 16.51. C18H18N4O3. Calculated, %: C 63.89; H 5.36;
N 16.56. M 338.14.
1
(C=O). H NMR spectrum, δ, ppm: 1.24 t (3H, CH3,
3J = 7.1 Hz), 3.23–3.31 m (1H, OCH2), 3.51–3.59 (1H,
OCH2), 7.30–7.65 m (7H, Harom, NH2), 8.85 s (1H,
N2H), 11.47 br.s (1H, N5H). 13C NMR spectrum, δC,
ppm: 15.6 (CH), 58.8 (CH), 80.6, 91.2, 93.5, 114.9,
126.6 (CH), 128.6 (CH), 129.1, 138.8, 151.9, 162.3,
165.8, 167.6. Mass spectrum, m/z (Irel, %): 310 (10)
[M]+, 265 (100) [M – OC2H5]+, 248 (22), 149 (46), 77
(71). Found, %: C 61.88; H 4.57; N 18.03. C16H14N4O3.
Calculated, %: C 61.93; H 4.55; N 18.06. M 310.11.
4-Amino-1-(2-methylpropyloxy)-3,6-dioxo-1-
phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyri-
dine-7-carbonitrile (3f). Yield 0.480 g (71%), white
powder, mp 179–181°C (decomp.). IR spectrum, ν,
cm–1: 3423, 3266, 3248 (NH, NH2), 2218 (C≡N), 1710,
4-Amino-3,6-dioxo-1-phenyl-1-propoxy-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carboni-
trile (3c). Yield 0.395 g (61%), white powder, mp 196–
198°C (decomp.). IR spectrum, ν, cm–1: 3513, 3437,
3306, 3244 (NH, NH2), 2224 (C≡N), 1710, 1661
1
1675 (C=O). H NMR spectrum, δ, ppm: 0.95 d (3H,
1
3
3
(C=O). H NMR spectrum, δ, ppm: 0.98 t (3H, CH3,
CH3, J = 6.7 Hz), 0.98 d (3H, CH3, J = 6.7 Hz),
3J = 7.3 Hz), 1.60–1.67 m (2H, CH2), 3.13–3.19 m
(1H, OCH2), 3.45–3.51 m (1H, OCH2), 7.20–7.70 m
(7H, Harom, NH2), 8.85 s (1H, N2H), 11.48 br.s (1H,
N5H). 13C NMR spectrum, δC, ppm: 11.3 (CH), 23.0
(CH), 64.5 (CH), 80.7, 91.0, 93.4, 114.9, 126.6 (CH),
128.6 (CH), 129.1, 138.8, 151.7, 162.3, 165.6, 167.5.
Mass spectrum, m/z (Irel, %): 324 (5) [M]+, 265 (27)
[M – OC3H7]+, 149 (14), 57 (100). Found, %: C 62.91;
H 4.99; N 17.25. C17H16N4O3. Calculated, %: C 62.95;
H 4.97; N 17.27. M 324.12.
3
1.91 sept (1H, CH, J = 6.6 Hz), 2.93–2.99 m (1H,
CH2), 3.30–3.33 m (1H, OCH2) (the signal was
partially overlapped by the water signal), 7.30–7.60 m
(7H, Harom, NH2), 8.83 s (1H, N2H), 11.50 br.s (1H,
N5H). 13C NMR spectrum, δC, ppm: 19.8 (CH), 20.0
(CH), 28.6 (CH), 69.1 (CH), 80.7 (CH), 90.9, 93.4,
114.9, 126.6 (CH), 128.6 (CH), 129.1, 138.9, 151.8,
162.3, 165.5, 167.5. Mass spectrum, m/z (Irel, %): 338
(7) [M]+, 265 (48) [M – OC4H9]+, 248 (12), 105 (16),
57 (100). Found, %: C 63.90; H 5.37; N 16.52.
C18H18N4O3. Calculated, %: C 63.89; H 5.36; N 16.56.
M 338.14.
4-Amino-3,6-dioxo-1-phenyl-1-(propan-2-yloxy)-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-car-
bonitril (3d). Yield 0.343 g (53%), white powder,
mp 198–200°C (decomp.). IR spectrum, ν, cm–1: 3513,
3406, 3279 (NH, NH2), 2219 (C≡N), 1687 (C=O).
The purity of the isolated compounds was checked
by TLC on Sorbfil PTSH-AF-A-UF plates; spots were
visualized under UV light (λ 254, 365 nm) and by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

KAYUKOV et al.
1114
2. Grigoreva, T.A., Novikova, D.S., Petukhov, A.V., Gure-
ev, M.A., Garabadzhiu, A.V., Melino, G., Barlev, N.A.,
and Tribulovich, V.G., Bioorg. Med. Chem. Lett., 2017,
vol. 27, p. 5197.
thermal decomposition. The IR spectra were recorded
in mineral oil on an FSM-1202 spectrometer with
1
Fourier transform. The H and 13C NMR spectra were
measured on a Bruker Avance III HD 400 spectrometer
at 400 MHz and 101 MHz, respectively, using
DMSO-d6 as solvent and tetramethylsilane as internal
standard. The mass spectra (electron impact, 70 eV)
were obtained with a Shimadzu GCMS-QP 2010 SE
instrument. Elemental analyses were carried out on
a Vario MICRO cube CHN analyzer. The melting
points were determined using an Electrothermal IA
9000 series II melting point apparatus. 4-Amino-1-
hydroxy-3,6-dioxo-1-phenyl-2,3,5,6-tetrahydro-1H-
pirrolo[3,4-c]pyridine-7-carbonitrile (2) was synthe-
sized according to [4].
https://doi.org/10.1016/j.bmcl.2017.10.049
3. Deraeve, C., Dorobantu, I.M., Rebbah, F., Le Qué-
méner, F., Constant, P., Quémard, A., Bernardes-
Génisson, V., Bernadou, J., and Pratviel, G., Bioorg.
Med. Chem., 2011, vol. 19, p. 6225.
https://doi.org/10.1016/j.bmc.2011.09.017
4. Kayukov, Ya.S., Bardasov, I.N., Karpov, S.V.,
Ershov, O.V., Nasakin, O.E., Kayukova, O.V., and
Tafeenko, V.A., Russ. J. Org. Chem., 2012, vol. 48,
p. 1447.
https://doi.org/10.1134/S1070428012110073
5. Grigor’ev, A.A., Karpov, S.V., Kayukov, Ya.S.,
Gracheva, I.A., and Tafeenko, V.A., Synlett, 2017,
vol. 28, p. 1592.
FUNDING
https://doi.org/10.1055/s-0036-1588823
6. Kayukov, Ya.S., Karpov, S.V., Grigor’ev, A.A., Nikifo-
rova, A.L., Nasakin, O.E., Shchegravina, E.S., Kayuko-
va, O.V., and Tafeenko, V.A., Chem. Heterocycl.
Compd., 2017, vol. 53, p. 568.
This study was performed under financial support by the
Russian Foundation for Basic Research (project no. 18-33-
01204 mol_a).
https://doi.org/10.1007/s10593-017-2093-x
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
7. Achari, K.M.M., Karthick, M., and Ramanathan, C.R.,
J. Chem. Sci., 2017, vol. 129, p. 679.
https://doi.org/10.1007/s12039-017-1301-7
8. Kadoh, Y., Oisaki, K., and Kanai, M., Chem. Pharm.
Bull., 2016, vol. 64, p. 737.
https://doi.org/10.1248/cpb.c16-00083
9. Mochalov, S.S., Fedotov, A.N., Trofimova, E.V., and
Zefirov, N.S., Russ. J. Org. Chem., 2018, vol. 54, p. 403.
https://doi.org/10.1134/S1070428018030065
10. Komori, K., Taniguchi, T., Mizutani, S., Monde, K.,
Kuramochi, K., and Tsubaki, K., Org. Lett., 2014,
vol. 16, p. 1386.
1. Lam, B., Arikawa, Y., Cramlett, J., Dong, Q., de Jong, R.,
Feher, V., Grimshaw, C.E., Farrell, P.J., Hoffman, I.D.,
Jennings, A., Jones, B., Matuszkiewicz, J., Miura, J.,
Miyake, H., Natala, S.R., Shi, L., Takahashi, M.,
Taylor, E., Wyrick, C., Yano, J., Zalevsky, J., and Nie, Z.,
Bioorg. Med. Chem. Lett., 2016, vol. 26, p. 5847.
https://doi.org/10.1016/j.bmcl.2016.10.087
https://doi.org/10.1021/ol500148g
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