Синтетичний підхід до спіропіранокумаринів та їх оксимів
This study explores the synthesis of a diverse series of linear (spiro)pyranocoumarins and their corresponding oximes, compounds known for their promising biological activities. Building on previous work, the authors expand the array of target compounds, adding structural features such as dimethyl g...
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| Дата: | 2023 |
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
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Ukrainica Bioorganica Acta| _version_ | 1871193593180323840 |
|---|---|
| author | Krasylov, Igor V. Moskvina, Viktoriia S. Khilya, Volodymyr P. |
| author_facet | Krasylov, Igor V. Moskvina, Viktoriia S. Khilya, Volodymyr P. |
| author_institution_txt_mv | [
{
"author": "Igor V. Krasylov",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "Viktoriia S. Moskvina",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Volodymyr P. Khilya",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
}
] |
| author_sort | Krasylov, Igor V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | This study explores the synthesis of a diverse series of linear (spiro)pyranocoumarins and their corresponding oximes, compounds known for their promising biological activities. Building on previous work, the authors expand the array of target compounds, adding structural features such as dimethyl groups and various cycloaliphatic rings. The novel synthetic procedure applied herein couples o-hydroxyacetyl coumarins with respective ketones via Kabbe condensation, yielding 16 derivatives, including 12 new compounds. A further step engages these (spiro)pyranocoumarins with hydroxylamine hydrochloride, leading to oximes, selectively at the exocyclic oxygen atom of the chroman-4-one fragment. Optimizing synthesis conditions has increased product yields and reduced reaction times. Acidic hydrolysis of select compounds introduces additional carbonyl groups and facilitates deprotection, while the subsequent reaction with hydroxylamine hydrochloride produces dual-oxime compounds. These findings contribute to the ongoing development of pyranocoumarin and oxime-based therapeutics, with potential applications in treating various diseases |
| doi_str_mv | 10.15407/bioorganica2023.01.042 |
| first_indexed | 2025-07-17T12:19:52Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
UDC 547.814.5/.304.6
DOI: https://doi.org/10.15407/bioorganica2023.01.042
42
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Synthetic approach to spiropyranocoumarins and their oxime derivatives
Igor V. Krasylov1, Viktoriia S. Moskvina1,2*, Volodymyr P. Khilya1
1 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
2 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: This study explores the synthesis of a diverse series of linear (spiro)pyranocoumarins and their corresponding oximes,
compounds known for their promising biological activities. Building on previous work, the authors expand the array of target compounds,
adding structural features such as dimethyl groups and various cycloaliphatic rings. The novel synthetic procedure applied herein couples
o-hydroxyacetyl coumarins with respective ketones via Kabbe condensation, yielding 16 derivatives, including 12 new compounds. A
further step engages these (spiro)pyranocoumarins with hydroxylamine hydrochloride, leading to oximes, selectively at the exocyclic
oxygen atom of the chroman-4-one fragment. Optimizing synthesis conditions has increased product yields and reduced reaction times.
Acidic hydrolysis of select compounds introduces additional carbonyl groups and facilitates deprotection, while the subsequent reaction
with hydroxylamine hydrochloride produces dual-oxime compounds. These findings contribute to the ongoing development of
pyranocoumarin and oxime-based therapeutics, with potential applications in treating various diseases.
Keywords: heterocyclization; coumarin; pyranocoumarin; spiropyranocoumarin; oxime.
Introduction
Pyranocoumarins, a class of naturally occurring oxygen-
containing heterocyclic compounds, are fundamental
building blocks in the synthesis of diverse natural products.
These compounds exhibit a multitude of biological
activities, including antifungal, insecticidal, anticancer,
anti-HIV, anti-inflammatory, antioxidant, and antibacterial
properties [1, 2]. Likewise, oximes, a versatile class of
nitrogen-containing compounds, display antibacterial,
antifungal, anti-inflammatory, antioxidant, and anticancer
properties, and play vital roles in plant metabolism and
biosynthetic pathways [3, 4]. The ease of synthesis and
potential for conversion into other heterocyclic compounds
further amplify their appeal in organic chemistry.
This publication discusses the synthesis of graveolone-
based pyranocoumarin analogs and their corresponding
Received:
Revised:
Accepted:
Published online:
16.04.2023
26.04.2023
30.05.2023
30.06.2023
Corresponding author. Tel.: +380-66-791-0921;
e-mail: v.moskvina@gmail.com (V.S. Moskvina)
ORCID: 0000-0001-5556-9147
oximes. In our prior work we have reported select
pyranocoumarins, spiropyranocoumarins and their oximes
[5-8], demonstrating their synthetic potential for amino acid
derivative synthesis [9]. Our current work presents an
expanded set of target compounds and illustrates the
synthesis of (spiro)pyranocoumarins and their oximes,
featuring dimethyl groups, cyclobutyl, cyclopentyl,
cyclohexyl, norbornanyl, and 4,4-difluorocyclohexyl rings.
Results and Discussion
The synthetic procedure devised for this study engaged
o-hydroxyacetyl coumarins 1 and 2 in Kabbe condensation
with respective ketones - acetone (3), cyclobutanone (4),
cyclopentanone (5), cyclohexanone (6), bicyclo[2.2.1]-
heptan-2-one (7), 1,4-dioxaspiro[4.5]decan-8-one (8), tert-
butyl 4-oxopiperidine-1-carboxylate (9) and 4,4-difluoro-
cyclohexan-1-one (10), utilizing pyrrolidine (Pyr) as the
base (Scheme 1). This approach consequently yielded 16
derivatives, including 12 novel compounds, with yields
ranging from 52 to 88% (Table 1). Importantly, optimizing
the reaction conditions enabled us to obtain previously
published products with higher yields than those reported in
the literature [6-9].
In 13C NMR spectra for compounds 11-26, a signal
ranging 72.3 to 88.8 ppm is observed, indicative of a
© Krasylov I.V. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:v.moskvina@gmail.com
https://orcid.org/0000-0001-5556-9147
I.V. Krasylov et al.
43
Table 1. Structures and yields of synthesized oximes 27-42.
Ketone
3-10
Pyranocoumarin 11-26 Yield, % Oxime 27-42 Yield, %
(3)
11: R = Me, 70%
12: R = Ph, 71%
(42% [6])
27: R = Me, 80%
28: R = Ph, 97%
(79% [7, 9])
(4)
13: R = Me, 63%
14: R = Ph, 70%
29: R = Me, 77%
30: R = Ph, 81%
(5)
15: R = Me, 72%
16: R = Ph, 70%
(57% [6, 8])
31: R = Me, 83%
32: R = Ph, 95%
(6)
17: R = Me, 85%
(85% [10])
18: R = Ph, 88%
(82% [6, 8])
33: R = Me, 96%
34: R = Ph, 98%
(92% [7])
(7)
19: R = Me, 52%
20: R = Ph, 61%
35: R = Me, 83%
36: R = Ph, 88%
(8)
21: R = Me, 81%
22: R = Ph, 85%
(69% [7])
37: R = Me, 95%
38: R = Ph, 75%
(75% [7])
(9)
23: R = Me, 86%
24: R = Ph, 87%
39: R = Me, 77%
40: R = Ph, 82%
(10)
25: R = Me, 80%
26: R = Ph, 87%
41: R = Me, 86%
42: R = Ph, 89%
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
44
O
R
O
Me
HO
O
R2
R1 O
Pyr, AcCN,
50 oC, 7-48 h
(3-8 eq.)
R=Me (1), R=Ph (2)
O
R
O
Me
O
O
R1
R2
11-26
O
R
O
Me
O
N
R1
R2
27-42
NH2OH·HCl
(3-10 eq.)
Py, 90 oC,
6-8 h
3-10
HO
Scheme 1. Synthesis of target (spiro)pyranocoumarins and their
oxime derivatives.
sprirocarbon (Figure 1). For norbornanone derivatives 19-
20, two peaks appear in this area due to a stereomeric
mixture of two compounds. The C4 carbon in compounds
25-26, which is directly bounded to fluorines resonates at δ
123.64 (t, J = 240.2 Hz), and the carbons ortho- and metha-
to the fluorines resonated at δ 30.80 (d, J = 9.2 Hz) and δ
29.32 (t, J = 24.7 Hz) respectively.
Subsequently, our investigation focused on optimizing
the synthesis method for the (spiro)pyranocoumarins'
oximes. Use of 1.5-2 equivalents of hydroxylamine
hydrochloride in pyridine resulted in low product yields (up
to 71%), while using 3-10 equivalents enhanced the target
product yields and reduced reaction time. Generally, the
interaction of (spiro)pyranocoumarins 11-26 was selective,
exclusively involving the exocyclic Oxygen atom of the
chroman-4-one fragment without affecting the exocyclic
Oxygen atom of the benzopyran-2-one system (Scheme 1).
The target products - oximes 27-42 - were obtained with
high yields (up to 98%) (Table 1).
The formation of oximes 27-42 was evidenced by the
appearance of singlets at 11.07-11.43 ppm in the 1H NMR
spectra, characteristic of the =NOH group; in the 13C NMR
spectra, the pyran carbonyl signal at 190.2-196.8 ppm is no
longer observed, replaced by a signal at 159.9-161.2 ppm,
which is characteristic of oxime carbon (Figure 1).
Compounds 47 and 48 contain additional oxime group, the
signals of which are at 11.19 and 11.26 ppm. The integrity
of the coumarin system was confirmed by the presence of
signals in the 1H NMR spectra, notably the characteristic
singlet of the benzopyran-2-one system at 6.09-6.24 ppm
(Figure 1).
O O
R
O
Me
R1
R2
O
72.3-88.8
190.2-196.8
6.17-6.34
11-26
O O
R
O
Me
R1
R2
N
75.93-88.24
6.09-6.24
27-42
HO
11.07-11.43
159.9-161.2
Figure 1. (Style a_Figure) Example of a single column figure
consisting of two panels. A) Graph.
Acidic hydrolysis of dioxolane fragment-containing
compounds 21-22 in methanol at 50º°C led to the formation
of compounds 43 and 44 with yields of 75% and 81%
respectively, featuring an additional carbonyl group
(Scheme 2). The hydrolysis of compounds 23 and 24 with a
Boc group under similar conditions was accompanied by
the removal of the protecting group, resulting in compounds
45 and 46 (Scheme 2). Importantly, optimizing the
conditions for the product extraction allowed us to obtain
products 44 and 46 with higher yields - 85% and 92%
respectively (compared to the previously described
methodology [7]).
21-22
O
R
O
Me
O
O
HCl,MeOH
Py, 50-55 oC,
3-4 h
O
R
O
Me
O
O
HN
O
23-24
45 (R = Me, 85 %),
46 (R = Ph, 92%)
43 (R = Me, 75%),
44 (R = Ph, 81%)
O
R
O
Me
O
N
O
R
O
Me
O
N
HN
N
49 (R = Me, 81%),
50 (R = Ph, 90%)
47 (R = Me, 58%),
48 (R = Ph, 49%)
HO
HO
NH2OH·HCl
(5-10 eq.)
Py, oC,
6-8 h
HO
Scheme 2. Synthesis of spiropyranocoumarins 43-46 and their oxime derivatives 47-50.
I.V. Krasylov et al.
45
The subsequent interaction of products 43-44 with 10
equivalents of hydroxylamine hydrochloride led to the
formation of compounds 47 (58%) and 48 (49%), which
contain two oxime groups. This is confirmed by the
presence of two characteristic signals for the OH groups of
oximes in the 1H NMR spectra at 10.3 and 11.2 ppm; the
interaction of spiropyranocoumarins 45 and 46 with
5 equivalents of hydroxylamine hydrochloride resulted in
the formation of corresponding oximes 49 and 50 with
yields of 81% and 90% respectively.
Conclusions
In conclusion, we have successfully synthesized a series
of linear (spiro)pyranocoumarins, each featuring distinctive
structural features such as dimethyl groups, cyclobutyl,
cyclopentyl, cyclohexyl, norbornanyl, 1,4-dioxaspiro-
[4.5]decane, tert-butyl 4-oxopiperidine-1-carboxylate and
4,4-difluorocyclohexyl cycles. We investigated the
interaction of the obtained (spiro)pyranocoumarins with
hydroxylamine hydrochloride, finding that the reaction
occurred selectively at the exocyclic oxygen atom of the
chroman-4-one fragment. The resulting oximes of
(spiro)pyranocoumarins are convenient reagents equipped
with additional functional groups for further structural
modification. The research enhances our understanding and
paves the way to the development of novel therapeutics
based on pyranocoumarin and oxime derivatives. Such
derivatives could be invaluable in treating a variety of
diseases, including bacterial infections, cancer, and
neurodegenerative disorders.
Experimental section
The 1H NMR (400 MHz) and 13C NMR (100 MHz)
experiments were conducted at 25 °C in DMSO-d6, using
TMS as internal standard on a Varian Mercury 400
spectrometer. Mass spectra were recorded on an LC-MS
instrument with chemical ionization (CI). LC-MS data were
acquired on an Agilent 1200 HPLC system equipped with
DAD/ELSD/LCMS-6120 diode matrix and mass-selective
detector. The course of reactions were monitored by TLC
on UV-254 Silufol plates using CHCl3-MeOH (95:5).
Melting points were determined on a Kofler-type Leica
Galen III micro hot stage microscope. All solvents were
purified using standard procedures.
General procedure for the synthesis of pyranocoumarins
11 and 12.
Solution of 10 mmol chromen-2-one (1, 2), acetone (3)
(80 mmol) and 25 mmol of pyrrolidine (Pyr) in acetonitrile
(35 ml) was heated at 50 °C for 12 h (TLC control of the
reaction). Then the reaction mixture cooled off, poured into
water (200 ml) and neutralized by HCl. The precipitate that
formed was filtered off, washed with H2O and crystallized
from 2-propanol.
4,8,8,10-Tetramethyl-7,8-dihydropyrano[3,2-g]-chrome-
ne-2,6-dione (11).
Yield: 70%; mp 140-142 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.43 (s, 6H), 2.18 (s, 3H), 2.41 (s, 3H), 2.86 (s,
2H), 6.29 (s, 1H), 7.93 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.37, 18.47, 26.60, 47.96, 80.99, 112.59,
113.72, 113.82, 116.63, 121.08, 153.74, 156.14, 159.54,
159.79, 191.55. APSI MS: 273.0 (M++1). Anal. Calcd for
C16H16O4: C, 70.57; H, 5.92%. Found: C, 70.65; H, 5.99%.
8,8,10-Trimethyl-4-phenyl-7,8-dihydropyrano[3,2-g]-
chromene-2,6-dione (12).
Yield: 71%; mp 185-186 °C [5, 6]. 1H NMR (400MHz,
DMSO-d6) δ 1.44 (s, 6H), 2.26 (s, 3H), 2.84 (s, 2H), 6.34 (s,
1H), 7.52 (m, 2H), 7.59 (m, 3H), 7.67 (s, 1H). 13C NMR
(100MHz, DMSO-d6) δ 8.60, 26.70, 49.50, 77.60, 111.60,
112.70, 116.90, 119.00, 123.20, 126.40, 128.00, 128.70,
140.00, 155.40, 155.60, 156.40, 160.80, 196.80. APSI MS:
335.2 (M++1). Anal. Calcd for C21H18O4: C, 75.43; H,
5.43%. Found: C, 75.57; H, 5.59%.
General procedure for the synthesis of spiropyrano-
coumarins 13-18.
Solution of 10 mmol chromen-2-one (1, 2), ketone 4-6
(50 mmol) and 25 mmol of pyrrolidine (Pyr) in acetonitrile
(35 ml) was heated at 50 °C for 24-48 h (TLC control of the
reaction). Then the reaction mixture cooled off, poured into
water (200 ml) and neutralized by HCl. The precipitate that
formed was filtered off, washed with H2O and crystallized
from 2-propanol.
6',10'-Dimethyl-8'H-spiro[cyclobutane-1,2'-pyrano[3,2-
g]chromene]-4',8'(3'H)-dione (13).
Yield: 63%; mp 120-122 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.71-1.86 (m, 2H), 2.10-2.25 (m, 4H), 2.16 (s,
3H), 2.34 (s, 3H), 3.00 (s, 2H), 6.24 (s, 1H), 7.83 (s, 1H).
13C NMR (100MHz, DMSO-d6) δ 8.39, 12.07, 18.46, 33.22,
45.31, 81.99, 112.80, 114.14, 114.29, 117.37, 121.29,
153.72, 156.09, 159.40, 159.49, 191.47. APSI MS: 285.0
(M++1). Anal. Calcd for C17H16O4: C, 71.82; H, 5.67%.
Found: C, 71.97; H, 5.74%.
10'-Methyl-6'-phenyl-8'H-spiro[cyclobutane-1,2'-pyra-
no[3,2-g]chromene]-4',8'(3'H)-dione (14).
Yield: 70%; mp 158-160 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.73-1.88 (m, 2H), 2.13 (m, 2H), 2.29 (m, 5H),
3.01 (s, 2H), 6.34 (s, 1H), 7.49 (m, 2H), 7.59 (m, 3H), 7.64
(s, 1H). 13C NMR (100MHz, DMSO-d6) δ 8.56, 12.05,
33.25, 45.23, 82.10, 113.07, 113.38, 114.73, 117.48,
123.14, 128.85, 129.38, 130.30, 135.10, 155.67, 156.73,
159.51, 159.55, 191.46. APSI MS: 347.0 (M++1). Anal.
Calcd for C22H18O4: C, 76.29; H, 5.24%. Found: C, 76.38;
H, 5.38%.
6',10'-Dimethyl-8'H-spiro[cyclopentane-1,2'-pyrano[3,2-
g]chromene]-4',8'(3'H)-dione (15).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
46
Yield: 72%; mp 146-148 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.67-1.76 (m, 6H), 1.91 (m, 2H), 2.10 (s, 3H),
2.35 (s, 3H), 2.92 (s, 2H), 6.23 (s, 1H), 7.84 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 8.23, 18.50, 23.68, 37.17,
45.94, 91.55, 112.64, 114.00, 114.12, 117.35, 121.29,
153.79, 156.04, 159.56, 160.03, 191.48. APSI MS: 299.2
(M++1). Anal. Calcd C18H18O4: C, 72.47; H, 6.08%. Found:
C, 72.58; H, 6.20%.
10'-Methyl-6'-phenyl-8'H-spiro[cyclopentane-1,2'-pyra-
no[3,2-g]chromene]-4',8'(3'H)-dione (16).
Yield: 70%; mp 212-214 °C [6]. 1H NMR (400MHz,
DMSO-d6) δ 1.66-1.87 (m, 6H), 2.01 (m, 2H), 2.27 (s, 3H),
2.83 (s, 2H), 6.18 (s, 1H), 7.44 (m, 2H), 7.54 (m, 3H), 7.69
(s, 1H). 13C NMR (100MHz, DMSO-d6) δ 9.80, 24.70,
40.10, 44.50, 77.70, 111.80, 112.80, 116.70, 119.30,
123.40, 127.30, 127.90, 128.60, 135.40, 155.10, 155.40,
156.20, 160.60, 190.90. APSI MS: 361.1 (M++1). Anal.
Calcd for C23H20O4: C, 76.65; H, 5.59%. Found: C, 76.78;
H, 5.67%.
6',10'-Dimethyl-8'H-spiro[cyclohexane-1,2'-pyrano[3,2-
g]-chromene]-4',8'(3'H)-dione (17).
Yield: 85%; mp 197-199 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.24-1.91 (m, 10H), 2.21 (s, 3H), 2.38 (s, 3H),
2.79 (s, 2H), 6.25 (s, 1H), 7.87 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.15, 18.37, 21.39, 24.84, 34.14, 47.72, 81.43,
112.50, 113.84, 117.13, 120.96, 153.67, 156.11, 159.13,
159.44, 191.36. APSI MS: 313.2 (M++1). Anal. Calcd for
C19H20O4: C, 73.06; H, 6.45% [10]. Found: C, 73.17; H,
6.54%.
10'-Methyl-6'-phenyl-8'H-spiro[cyclohexane-1,2'-pyra-
no[3,2-g]chromene]-4',8'(3'H)-dione (18).
Yield: 88%; mp 249-251 °C [10]. 1H NMR (400MHz,
DMSO-d6) δ 1.24-1.91 (10H, m, CH2-2, CH2-3, CH2-4,
CH2-5, CH2-6), 2.27 (3H, s, CH3-10'), 2.76 (2H, s, CH2-3'),
6.30 (1H, s, H-7'), 7.48 (2H, m, H-2'', H-6''), 7.56 (3H, m,
Н-3'', Н-4'', Н-5''), 7.62 (1H, s, H-5'). 13C NMR (100MHz,
DMSO-d6) δ 8.45, 21.51, 24.94, 34.23, 40.85, 47.78, 81.78,
112.83, 113.00, 114.52, 117.39, 122.97, 128.87, 129.37,
130.29, 135.18, 155.78, 156.83, 159.41, 191.50. APSI MS:
375.2 (M++1). Anal. Calcd for C24H22O4: C, 76.99; H,
5.92%. Found: C, 77.57; H, 6.04%.
General procedure for the synthesis of
spiropyranocoumarins 19-26.
Solution of 10 mmol chromen-2-one (1, 2), ketone 7-10
(30 mmol) and 25 mmol of pyrrolidine (Pyr) in acetonitrile
(35 ml) was heated at 50 °C for 20-36 h (TLC control of the
reaction). Then the reaction mixture cooled off, poured into
water (200 ml) and neutralized by HCl. The precipitate that
formed was filtered off, washed with H2O and crystallized
from 2-propanol.
6',10'-Dimethyl-8'H-spiro[bicyclo[2.2.1]heptane-2,2'-py-
rano[3,2-g]chromene]-4',8'(3'H)-dione (19).
Yield: 52%; mp 142-143 °C. 1H NMR (400MHz,
DMSO-d6) δ 0.75-1.98 (m, 8H), 2.23-2.26 (bs, 3H), 2.34
(m, 1H), 2.39 (m, 1H), 2.42 (s, 3H), 2.73-2.94 (m, 2H), 6.17
(s, 1H), 7.89 (s, 1H). 13C NMR (100MHz, DMSO-d6) δ
8.25, 8.36, 18.48, 22.47, 27.73, 27.98, 36.29, 36.53, 37.33,
43.74, 44.05, 44.47, 44.75, 45.12, 47.42, 88.60, 89.88,
112.67, 113.77, 114.01, 114.19, 117.58, 117.70, 121.16,
121.29, 153.77, 156.03, 159.53, 159.86, 160.45, 191.32,
191.49. APSI MS: 325.0 (M++1). Anal. Calcd for C20H20O4:
C, 74.06; H, 6.21%. Found: C, 74.26; H, 6.44%.
10'-Methyl-6'-phenyl-8'H-spiro[bicyclo[2.2.1]heptane-
2,2'-pyrano[3,2-g]chromene]-4',8'(3'H)-dione (20).
Yield: 61%; mp 191-192 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.11-1.97 (m, 8H), 2.30-2.33 (bs, 3H), 2.34
(m, 1H), 2.40 (m, 1H), 2.72-2.89 (m, 2H), 6.19 (s, 1H), 7.45
(m, 2H), 7.55 (m, 3H), 7.68 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.44, 8.54, 22.51, 25.93, 27.72, 28.01, 36.29,
36.52, 37.34, 43.70, 44.10, 44.41, 44.79, 45.07, 47.37,
88.81, 90.09, 112.88, 113.07, 114.78, 117.85, 123.04,
123.14, 128.86, 129.37, 130.29, 135.13, 155.74, 156.67,
159.54, 160.06, 160.62, 191.34, 191.48. APSI MS: 387.2
(M++1). Anal. Calcd for C25H22O4: C, 77.70; H, 5.74%.
Found: C, 77.91; H, 5.88%.
6,10-Dimethyl-8H-dispiro[pyrano[3,2-g]chromene-2,1'-
cyclohexane-4',2''[1,3]dioxolane]-4,8(3H)-dione (21).
Yield: 81%; mp 173-174 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.53-2.05 (m, 8H), 2.31 (s, 3H), 2.44 (s, 3H),
2.74 (s, 2H), 3.88 (s, 4H), 6.17 (s, 1H), 7.91 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 10.7, 21.5, 27.6×2, 34.4,
45.1, 65.7, 71.2, 72.3, 112.6, 113.4, 117.5, 118.95, 120.1,
123.6, 153.8, 156.6, 157.3, 158.8, 161.3, 191.2. APSI MS:
371.0 (M++1). Anal. Calcd for C21H22O6: C, 68.10; H,
5.99%. Found: C, 69.37; H, 6.20%.
10-Methyl-6-phenyl-8H-dispiro[pyrano[3,2-g]chromene-
2,1'-cyclohexane-4',2''-[1,3]dioxolane]-4,8(3H)-dione (22).
Yield: 87%; mp 222-223 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 1.57-2.02 (m, 8H), 2.36 (s, 3H), 2.56 (s, 2H),
3.90 (s, 4H), 6.23 (s, 1H), 7.46 (m, 2H), 7.57 (m, 3H), 7.71
(s, 1H'). 13C NMR (100MHz, DMSO-d6) δ 8.40, 30.40,
32.10, 47.10, 64.20, 80.90, 107.30, 112.90, 113.30, 114.70,
123.00, 129.20, 129.90, 130.70, 155.60, 156.90, 159.20,
159.50, 191.10. APSI MS: 433.0 (M++1). Anal. Calcd for
C26H24O6: C, 72.21; H, 5.59%. Found: C, 72.43; H, 5.70%.
tert-Butyl 6',10'-dimethyl-4',8'-dioxo-3',4'-dihydro-8'H-
spiro[piperidine-4,2'-pyrano[3,2-g]chromene]-1-carboxy-
late (23).
Yield: 86%; mp 177-178 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.41 (s, 9H), 1.68 (m, 2H), 1.93 (m, 2H), 2.30
(s, 3H), 2.44 (s, 3H), 2.81 (s, 2H), 3.14 (m, 2H), 3.82 (m,
I.V. Krasylov et al.
47
2H), 6.21 (s, 1H), 7.92 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.05, 18.10, 27.92, 46.50, 78.79, 79.32,
112.49, 112.76, 114.32, 116.91, 122.49, 133.8, 153.60,
155.21, 156.45, 158.50, 158.87, 190.21. APSI MS: 414.2
(M++1). Anal. Calcd for C23H27NO6: C, 66.81; H, 6.58; N,
3.39%. Found: C, 66.95; H, 6.67%; N, 3.48%.
tert-Butyl 10'-methyl-4',8'-dioxo-6'-phenyl-3',4'-dihydro-
8'H-spiro[piperidine-4,2'-pyrano[3,2-g]chromene]-1-car-
boxylate (24).
Yield: 87%; mp 228-229 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.42 (s, 9H), 1.68 (m, 2H), 1.93 (m, 2H), 2.37
(s, 3H), 2.78 (s, 2H), 3.17 (m, 2H), 3.84 (m, 2H), 6.22 (s,
1H), 7.45 (m, 2H), 7.56 (m, 3H), 7.71 (1H, s, H-5'). 13C
NMR (100MHz, DMSO-d6) δ 7.99, 28.00, 46.49, 78.84,
79.44, 112.50, 112.75, 114.24, 116.82, 122.53, 128.35,
128.89, 129.82, 134.61, 153.66, 155.18, 156.34, 158.51,
158.98, 190.43. APSI MS: 476.3 (M++1). Anal. Calcd for
C28H29NO6: C, 70.72; H, 6.15; N, 2.95%. Found: C, 70.95;
H, 6.23%; N, 3.08%.
4,4-Difluoro-6',10'-dimethyl-8'H-spiro[cyclohexane-1,2'-
pyrano[3,2-g]chromene]-4',8'(3'H)-dione (25).
Yield: 80%; mp 202-203 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.75-2.09 (m, 8H), 2.21 (s, 3H), 2.36 (s, 3H),
2.92 (s, 2H), 6.28 (s, 1H), 7.90 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.23, 18.53, 29.06, 29.31, 29.55, 30.74, 30.83,
46.41, 79.70, 112.83, 114.22, 114.40, 117.12, 121.35,
123.67, 126.05, 153.94, 156.32, 158.69, 159.66, 191.04.
APSI MS: 349.2 (M++1). Anal. Calcd for C19H18F2O4: C,
65.51; H, 5.21%. Found: C, 65.67; H, 5.34%.
4,4-Difluoro-10'-methyl-6'-phenyl-8'H-spiro[cyclohexa-
ne-1,2'-pyrano[3,2-g]chromene]-4',8'(3'H)-dione (26).
Yield: 80%; mp 251-252 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.73-2.09 (m, 8H), 2.27 (s, 3H), 2.89 (s, 2H),
6.32 (s, 1H), 7.47 (m, 2H), 7.57 (m, 3H), 7.65 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 8.35, 29.08, 29.33, 29.57,
30.76, 30.85, 46.32, 79.89, 113.06, 113.36, 114.74, 117.21,
121.25, 123.14, 123.63, 126.02, 128.86, 129.39, 130.34,
135.08, 155.66, 156.89, 158.80, 159.46, 190.83. APSI MS:
411.0 (M++1). Anal. Calcd for C19H20F2O4: C, 70.24; H,
4.91%. Found: C, 70.39; H, 5.08%.
General procedure for the synthesis of oximes 27-42.
Solution of compound 11-26 (5 mmol) and
hydroxylamine hydrochloride (50 mmol) in pyridine (30
ml) was stirred for 8 hours at 80 °C. The course of the
reaction was monitored by TLC. Then reaction mixture was
cooled to room temperature and poured into water (200 ml)
and concentrated hydrochloric acid was added to pH 10.
After 30 minutes, the formed precipitate was filtered off,
washed with water and crystallized from 2-propanol.
6-(Hydroxyimino)-4,8,8,10-tetramethyl-7,8-dihydro-2H,-
6H-pyrano[3,2-g]chromen-2-one (27).
Yield: 80%; mp 248-250 °C [9]. 1H NMR (400MHz,
DMSO-d6) δ 1.31 (s, 6H), 2.09 (s, 3H), 2.32 (s, 2H), 2.79 (s,
2H), 6.17 (s, 1H), 7.85 (s, 1H), 11.34 (s, 1H). 13C NMR
(100MHz, DMSO-d6) δ 8.39, 18.48, 26.45, 26.94, 33.37,
77.14, 112.17, 113.33, 113.55, 114.98, 116.97, 146.78,
152.80, 153.64, 154.91, 160.16. APSI MS: 288.2 (M++1).
Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88%.
Found: C, 66.98; H, 6.07%; N, 4.98%.
6-(Hydroxyimino)-8,8,10-trimethyl-4-phenyl-7,8-dihyd-
ro-2H,6H-pyrano[3,2-g]chromen-2-one (28).
Yield: 97%; mp 250-252 °C [9]. 1H NMR (400MHz,
DMSO-d6) δ 1.32 (s, 6H), 2.17 (s, 3H), 2.76 (s, 2H), 6.20 (s,
1H), 7.47 (m, 2H), 7.53 (m, 3H), 7.69 (s, 1H), 11.32 (s,
1H). 13C NMR (100MHz, DMSO-d6) δ 8.52, 26.95, 33.36,
77.36, 112.26, 112.65, 113.87, 115.16, 119.11, 128.82,
129.27, 129.99, 135.61, 146.61, 153.44, 155.16, 155.97,
160.09. APSI MS: 350.0 (M++1). Anal. Calcd for
C21H19NO4: C, 72.19; H, 5.48; N, 4.01%. Found: C, 72.25;
H, 5.57%; N, 4.22%.
4'-(Hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-8'H-spi-
ro[cyclobutane-1,2'-pyrano[3,2-g]chromen]-8'-one (29).
Yield: 77%; mp 223-225 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.72 (m, 1H), 1.81 (m, 1H), 2.01 (m, 2H, ),
2.14 (m, 2H), 2.17 (s, 3H), 2.35 (s, 3H), 2.98 (s, 2H), 6.23
(s, 1H), 7.89 (s, 1H), 11.43 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.48, 12.20, 18.53, 31.05, 33.45, 78.87,
112.47, 113.86, 114.10, 115.81, 117.16, 146.68, 152.77,
153.74, 154.64, 160.17. APSI MS: 300.2 (M++1). Anal.
Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68%. Found:
C, 68.34; H, 5.86%; N, 4.77%.
4'-(Hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihydro-
8'H-spiro[cyclobutane-1,2'-pyrano[3,2-g]chromen]-8'-one
(30).
Yield: 81%; mp 233-235 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.70 (m, 1H), 1.81 (m, 1H), 2.00 (m, 2H), 2.17
(m, 2H), 2.22 (s, 3H), 2.93 (s, 2H), 6.22 (s, 1H), 7.46 (m,
2H), 7.52 (m, 3H), 7.67 (s, 1H), 11.39 (s, 1H). 13C NMR
(100MHz, DMSO-d6) δ 8.54, 12.20, 30.95, 33.48, 78.96,
112.54, 113.14, 114.33, 115.89, 119.15, 128.79, 129.27,
129.99, 135.56, 146.46, 153.33, 154.81, 155.92, 160.04.
APSI MS: 362.0 (M++1). Anal. Calcd for C22H19NO4: C,
73.12; H, 5.30; N, 3.88%. Found: C, 73.28; H, 5.48%; N,
4.05%.
4'-(Hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-8'H-spi-
ro[cyclopentane-1,2'-pyrano[3,2-g]chromen]-8'-one (31).
Yield: 83%; mp 221-223 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.58-1.76 (m, 8H), 2.08 (s, 3H), 2.32 (s, 3H),
2.88 (s, 2H), 6.17 (s, 1H), 7.85 (s, 1H), 11.34 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 8.25, 18.48, 23.89, 31.53,
37.51, 88.06, 112.23, 113.72, 113.76, 115.78, 117.05,
147.06, 152.70, 153.65, 155.12, 160.15. APSI MS: 314.2
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
48
(M++1). Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N,
4.47%. Found: C, 69.98; H, 6.27%; N, 4.55%.
4'-(Hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihydro-
8'H-spiro[cyclopentane-1,2'-pyrano[3,2-g]chromen]-8'-one
(32).
Yield: 95%; mp 250-252 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.60-1.85 (m, 8H), 2.22 (s, 3H), 2.84 (s, 2H),
6.10 (s, 1H), 7.42 (m, 2H), 7,51 (m, 3H), 7.70 (s, 1H), 11.15
(s, 1H). 13C NMR (100MHz, DMSO-d6) δ 8.37, 23.87,
31.48, 37.51, 88.24, 112.31, 112.80, 114.29, 115.93,
119.17, 128.81, 129.26, 129.99, 135.60, 146.87, 153.33,
155.34, 155.96, 160.06. APSI MS: 376.0 (M++1). Anal.
Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73%. Found:
C, 73.67; H, 5.78%; N, 3.85%.
4'-(Hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-8'H-spi-
ro[cyclohexane-1,2'-pyrano[3,2-g]chromen]-8'-one (33).
Yield: 96%; mp 237-239 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.27-1.84 (m, 10H), 2.25 (s, 3H), 2.39 (s, 3H),
2.74 (s, 2H), 6.09 (s, 1H), 7.89 (s, 1H), 11.07 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 8.36, 18.53, 21.66, 25.15,
33.20, 34.62, 77.68, 112.24, 113.58, 113.71, 115.72,
117.00, 146.52, 152.92, 153.75, 154.32, 160.20. APSI MS:
328.0 (M++1). Anal. Calcd for C19H21NO4: C, 69.71; H,
6.47; N, 4.28%. Found: C, 70.07; H, 6.58%; N, 4.37%.
4'-(Hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihydro-
8'H-spiro[cyclohexane-1,2'-pyrano[3,2-g]chromen]-8'-one
(34).
Yield: 98%; mp 129-131 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.21-1.71 (m, 10H), 2.20 (s, 3H), 2.68 (s, 2H),
6.16 (s, 1H), 7.43 (m, 2H), 7.51 (m, 3H), 7.66 (s, 1H), 11.29
(s, 1H). 13C NMR (100MHz, DMSO-d6) δ 8.37, 21.65,
25.12, 33.09, 34.61, 77.75, 112.22, 112.66, 114.03, 115.78,
118.99, 128.78, 129.22, 129.95, 135.61, 146.23, 153.46,
154.46, 155.91, 160.01. APSI MS: 390.2 (M++1). Anal.
Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60%. Found:
C, 74.17; H, 6.08%; N, 3.75%.
4'-(Hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-8'H-spi-
ro[bicyclo[2.2.1]heptane-2,2'-pyrano[3,2-g]chromen]-8'-
one (35).
Yield: 72%; mp 136-137 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.05-1.85 (m, 8H), 2.08-2.12 (bs, 3H), 2.14
(m, 1H), 2.24 (m, 1H), 2.32 (s, 3H), 2.61-3.05 (m, 2H), 6.17
(s, 1H), 7.82 (s, 1H), 11.36 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.25, 8.36, 18.48, 22.40, 22.91, 27.82, 28.07,
28.74, 32.68, 36.41, 36.57, 37.29, 37.90, 44.43, 44.77,
45.00, 45.23, 85.18, 86.57, 112.22, 113.35, 113.68, 113.73,
113.83, 116.06, 116.99, 124.72, 137.71, 146.81, 146.89,
149.16, 152.68, 153.65, 155.05, 155.65, 160.14. APSI MS:
340.0 (M++1). Anal. Calcd for C20H21NO4: C, 70.78; H,
6.24; N, 4.13%. Found: C, 70.89; H, 6.38%; N, 4.25%.
4'-(Hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihydro-
8'H-spiro[bicyclo[2.2.1]heptane-2,2'-pyrano[3,2-g]chro-
men]-8'-one (36).
Yield: 78%; mp 219-220 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.04-1.88 (m, 8H), 2.16-2.20 (bs, 3H), 2.24
(m, 2H), 2.63-3.02 (m, 2H), 6.18 (s, 1H), 7.45 (m, 2H), 7.52
(m, 3H), 7.65 (s, 1H), 11.32 (s, 1H). 13C NMR (100MHz,
DMSO-d6) δ 8.37, 8.48, 22.46, 22.93, 27.81, 28.08, 28.69,
32.63, 36.42, 36.57, 37.28, 37.89, 44.44, 44.75, 44.97,
45.25, 85.35, 86.76, 112.28, 112.41, 112.76, 112.93,
113.88, 114.24, 116.21, 119.10, 128.79, 129.25, 129.97,
135.58, 146.68, 153.32, 155.29, 155.94, 160.03. APSI MS:
402.0 (M++1). Anal. Calcd for C25H23NO4: C, 74.79; H,
5.77; N, 3,49%. Found: C, 74.87; H, 5.88%; N, 3.58%.
4-(Hydroxyimino)-6,10-dimethyl-3,4-dihydro-8H-dispi-
ro[pyrano[3,2-g]chromene-2,1'-cyclohexane-4',2''-[1,3]-
dioxolan]-8-one (37).
Yield: 86%; mp 222-223 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.48-1.88 (m, 8H), 2.23 (s, 3H), 2.37 (s, 3H),
2.76 (s, 2H), 3.85 (s, 4H), 6.11 (s, 1H), 7.89 (s, 1H), 11.16
(s, 1H). 13C NMR (100MHz, DMSO-d6) δ 10.4, 20.7,
28.3×2, 30.2, 34.1×2, 64.6×2, 78.6, 112.8, 113.7, 114.3,
119.3, 120.2, 126.3, 148.3, 153.8, 155.7, 156.9, 161.2. APSI
MS: 386.0 (M++1). Anal. Calcd for C21H23NO6: C, 65.44;
H, 6.02, N, 3.63. Found: C, 65.57; H, 6.18%; N, 3.75%.
4-(Hydroxyimino)-10-methyl-6-phenyl-3,4-dihydro-8H-
dispiro[pyrano[3,2-g]chromene-2,1'-cyclohexane-4',2''-
[1,3]dioxolan]-8-one (38).
Yield: 82%; mp 235-236 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 1.56-1.88 (m, 8H), 2.32 (s, 3H), 2.56 (s, 2H),
3.88 (s, 4H), 6.15 (s, 1H), 7.45 (m, 2H), 7.54 (m, 3H), 7.76
(s, 1H), 11.28 (s, 1H). 13C NMR (100MHz, DMSO-d6) δ
8.31, 25.92, 30.41, 32.60, 64.20, 77.10, 107.70, 112.42,
113.11, 115.81, 119.20, 128.83, 129.30, 129.90, 146.20,
153.51, 154,40, 156.13, 160.11. APSI MS: 448.0 (M++1).
Anal. Calcd for C26H25NO6: C, 69.79; H, 5.63; N, 3.13.
Found: C, 69.88; H, 5.78%; N, 3.27%.
tert-Butyl 4'-(hydroxyimino)-6',10'-dimethyl-8'-oxo-3',4'-
dihydro-8'H-spiro[piperidine-4,2'-pyrano[3,2-g]-chrome-
ne]-1-carboxylate (39).
Yield: 84%; mp 201-202 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.39 (s, 9H), 1.65 (m, 2H), 1.81 (m, 2H), 2.31
(s, 3H), 2.42 (s, 3H), 2.79 (s, 2H), 3.13 (m, 2H), 3.79 (m,
2H), 6.12 (s, 1H), 7.79 (s, 1H), 11.11 (s, 1H). APSI MS:
429.0 (M++1). Anal. Calcd for C23H28N2O6: C, 64.47; H,
6.59; N, 6.54. Found: C, 64.56; H, 6.68%; N, 6.63%.
tert-Butyl 4'-(hydroxyimino)-10'-methyl-8'-oxo-6'-phe-
nyl-3',4'-dihydro-8'H-spiro[piperidine-4,2'-pyrano[3,2-g]-
chromene]-1-carboxylate (40).
I.V. Krasylov et al.
49
Yield: 82%; mp 229-230 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 1.40 (s, 9H), 1.59 (m, 2H), 1.79 (m, 2H), 2.33
(s, 3H), 2.77 (s, 2H), 3.14 (m, 2H), 3.81 (m, 2H), 6.13 (s,
1H), 7.44 (m, 2H), 7.52 (m, 3H), 7.72 (s, 1H), 11.22 (s,
1H). 13C NMR (100MHz, DMSO-d6) δ 8.81, 28.62, 32.80,
40.04, 76.12, 79.21, 112.60, 113.01, 114.40, 115,81,
119.03, 129.51, 130.42, 130.80, 153.62, 154.10, 154.31,
155.82, 160.01. APSI MS: 491.0 (M++1). Anal. Calcd for
C28H30N2O6: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.66;
H, 6.28%; N, 5.84%.
4,4-Difluoro-4'-(hydroxyimino)-6',10'-dimethyl-3',4'-di-
hydro-8'H-spiro[cyclohexane-1,2'-pyrano[3,2-g]-chro-
men]-8'-one (41).
Yield: 87%; mp >255 °C. 1H NMR (400MHz, DMSO-
d6) δ 1.66-2.00 (m, 8H), 2.16 (s, 3H), 2.32 (s, 3H), 2.83 (s,
2H), 6.20 (s, 1H), 7.87 (s, 1H), 11.42 (s, 1H). 13C NMR
(100MHz, DMSO-d6) δ 8.21, 18.49, 29.17, 29.42, 29.66,
31.03, 31.12, 32.18, 75.93, 112.51, 113.74, 114.11, 115.54,
117.07, 121.46, 123.84, 126.23, 145.92, 152.89, 153.53,
153.60, 160.05. APSI MS: 364.2 (M++1). Anal. Calcd for
C19H19F2NO4: C, 62.80; H, 5.27; N, 3.85%. Found: C,
62.96; H, 5.38%; N, 3.99%.
4,4-Difluoro-4'-(hydroxyimino)-10'-methyl-6'-phenyl-
3',4'-dihydro-8'H-spiro[cyclohexane-1,2'-pyrano[3,2-g]-
chromen]-8'-one (42).
Yield: 92%; mp >255 °C. 1H NMR (400MHz, DMSO-
d6) δ 1.65-2.05 (m, 8H), 2.24 (s, 3H), 2.82 (s, 2H), 6.24 (s,
1H), 7.47 (m, 2H), 7.53 (m, 3H), 7.72 (s, 1H), 11.42 (s,
1H). 13C NMR (100MHz, DMSO-d6) δ 8.33, 29.18, 29.42,
29.67, 31.04, 31.13, 32.17, 76.13, 112.61, 113.20, 114.27,
115.69, 119.17, 121.46, 123.85, 126.24, 128.81, 129.29,
130.04, 135.53, 145.76, 153.51, 153.76, 155.88, 159.99.
APSI MS: 426.0 (M++1). Anal. Calcd for C24H21F2NO4: C,
67.76; H, 4.98; N, 3.29%. Found: C, 67.88; H, 5.04%; N,
3.37%.
General procedure for the synthesis of pyranocoumarins
43-46.
To 1 mmol of compound 21-24 was added solution of
methanol (5 ml), concentrated hydrochloric acid (1 ml) and
heated to 50°C for 4 hours. Then the reaction mixture was
cooled and evaporated under vacuum. Formed precipitate
crystallized in methanol.
6',10'-Dimethyl-8'H-spiro[cyclohexane-1,2'-pyrano[3,2-
g]chromene]-4,4',8'(3'H)-trione (43).
Yield: 75%; mp 233-234 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.62-2.40 (m, 8H), 2.28 (s, 3H), 2.41 (s, 3H),
2.81 (s, 2H), 6.20 (s, 1H), 7.92 (s, 1H). APSI MS: 327.0
(M++1). Anal. Calcd for C19H18O5: C, 69.93; H, 5.56%.
Found: C, 70.07; H, 5.67%.
10'-Methyl-6'-phenyl-8'H-spiro[cyclohexane-1,2'-pyra-
no[3,2-g]chromene]-4,4',8'(3'H)-trione (44).
Yield: 81%; mp >255 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 2.11-2.37 (m, 8H), 2.39 (s, 3H), 2.89 (s, 2H),
6.25 (s, 1H), 7.48 (m, 2H), 7.58 (m, 3H), 7.74 (s, 1H). 13C
NMR (100MHz, DMSO-d6) δ 8.42, 34.61, 36.42, 46.44,
80.50, 113.03, 113.52, 114.05, 115.01, 123.05, 129.71,
130.54, 131.01, 156.91, 159.22, 159.69, 160.03, 190.12,
209.31. APSI MS: 389.0 (M++1). Anal. Calcd for C24H20O5:
C, 74.21; H, 5.19%. Found: C, 74.37; H, 5.28%.
6',10'-Dimethyl-8'H-spiro[piperidine-4,2'-pyrano[3,2-g]-
chromene]-4',8'(3'H)-dione (45).
Yield: 85%; mp >255 °C. 1H NMR (400MHz, DMSO-
d6) δ 2.01 (m, 2H), 2.12 (m, 2H), 2.28 (s, 3H), 2.42 (s, 3H),
2.97 (s, 2H), 3.08 (m, 2H), 3.21 (m, 2H), 6.33 (s, 1H), 7.95
(s, 1H), 9.30 (s, 2H). 13C NMR (100MHz, DMSO-d6) δ
7.94, 18.04, 30.17, 46.25, 77.26, 112.48, 113.86, 114.08,
116.58, 120.90, 153.36, 155.88, 157.94, 159.01, 189.84;
APSI MS: 314.0 (M++1). Anal. Calcd for C18H20ClNO4: C,
61.80; H, 5.76; Cl, 10.13; N, 4.00%. Found: C, 62.58; H,
5.89; Cl, 11.01; N, 4.13%.
10'-Methyl-6'-phenyl-8'H-spiro[piperidine-4,2'-pyrano-
[3,2-g]chromene]-4',8'(3'H)-dione (46).
Yield: 92%; mp >255 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 1.95 (m, 2H), 2.10 (m, 2H), 2.33 (s, 3H), 2.93
(s, 2H), 3.07 (m, 2H), 3.19 (m, 2H), 6.37 (s, 1H), 7.49 (m,
2H), 7.58 (m, 3H), 7.66 (s, 1H), 9.14 (s, 2H). 13C NMR
(100MHz, DMSO-d6) δ 8.07, 30.20, 46.12, 77.44, 112.73,
113.05, 114.41, 116.66, 122.66, 128.36, 128.95, 129.90,
134.55, 155.15, 156.41, 158.05, 158.97, 189.83. APSI MS:
376.0 (M++1). Anal. Calcd for C23H22ClNO4: C, 67.07; H,
5.38; Cl, 9.61; N, 3.40%. Found: C, 67.32; H, 5.46; Cl,
9.55; N, 3.57%.
4,4'-Bis(hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-
8'H-spiro[cyclohexane-1,2'-pyrano[3,2-g]chromen]-8'-one
(47).
Solution of compound 43 (1 mmol) and hydroxylamine
hydrochloride (10 mmol) in pyridine (20 ml) was stirred for
8 hours at 80 °C. The course of the reaction was monitored
by TLC. Then reaction mixture was cooled to room
temperature and poured into water (150 ml) and
concentrated hydrochloric acid was added to pH 10. After
30 minutes, the formed precipitate was filtered off, washed
with water and crystallized from 2-propanol.Yield: 58%.
mp >255 °C. 1H NMR (400MHz, DMSO-d6) δ 1.48-2.01
(m, 8H), 2.31 (s, 3H), 2.39 (s, 3H), 2.71 (s, 2H), 6.23 (s,
1H), 7.69 (s, 1H), 10.32 (s, 1H), 11.19 (s, 1H). APSI MS:
357.0 (M++1). Anal. Calcd for C19H20N2O5: C, 64.04; H,
5.66; N. 7.86. Found: C, 64.17; H, 5.79; N, 7.97%.
4,4'-Bis(hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihyd-
ro-8'H-spiro[cyclohexane-1,2'-pyrano[3,2-g]chromen]-8'-
one (48).
Solution of compound 44 (1 mmol) and hydroxylamine
hydrochloride (10 mmol) in pyridine (20 ml) was stirred for
8 hours at 80 °C. The course of the reaction was monitored
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
50
by TLC. Then reaction mixture was cooled to room
temperature and poured into water (150 ml) and
concentrated hydrochloric acid was added to pH 10. After
30 minutes, the formed precipitate was filtered off, washed
with water and crystallized from 2-propanol. Yield: 49%;
mp 187-188 °C [7]. 1H NMR (400MHz, DMSO-d6) δ 1.69-
2.24 (m, 8H), 2.36 (s, 3H), 2.82 (s, 2H), 6.16 (s, 1H), 7.48
(m, 2H), 7.56 (m, 3H), 7.77 (s, 1H), 10.28 (s, 1H), 11.26 (s,
1H). APSI MS: 419.0 (M++1). Anal. Calcd for C24H22N2O5:
C, 68.89; H, 5.30; N. 6.69. Found: C, 68.97; H, 5.49; N,
6.84%.
General procedure for the synthesis of 49 and 50.
Solution of compound 45 or 46 (1 mmol) and
hydroxylamine hydrochloride (5 mmol) in pyridine (20 ml)
was stirred for 8 hours at 80 °C. The course of the reaction
was monitored by TLC. Then reaction mixture was cooled
to room temperature and poured into water (100 ml) and
concentrated hydrochloric acid was added to pH 10. After
30 minutes, the formed precipitate was filtered off, washed
with water and crystallized from 2-propanol.
4'-(Hydroxyimino)-6',10'-dimethyl-3',4'-dihydro-8'H-spi-
ro[piperidine-4,2'-pyrano[3,2-g]chromen]-8'-one (49).
Yield: 81%; mp 157-158 °C. 1H NMR (400MHz,
DMSO-d6) δ 1.95 (m, 4H), 2.23 (s, 3H), 2.36 (s, 3H), 2.87
(s, 2H), 3.00 (m, 2H), 3.16 (m, 2H), 6.25 (s, 1H), 7.91 (s,
1H), 9.12 (s, 1H), 9.30 (s, 1H), 11.54 (s, 1H). 13C NMR
(100MHz, DMSO-d6) δ 8.47, 18.55, 30.86, 32.46, 46.73,
74.08, 112.66, 113.94, 114.32, 115.39, 117.21, 145.32,
148.95, 153.25, 153.70, 160.08. APSI MS: 329.0 (M++1).
Anal. Calcd for C18H21ClN2O4: C, 59.26; H, 5.80; Cl, 9.72;
N, 7.68. Found: C, 60.10; H, 5.95; Cl, 9.85; N, 7.76%.
4'-(Hydroxyimino)-10'-methyl-6'-phenyl-3',4'-dihydro-
8'H-spiro[piperidine-4,2'-pyrano[3,2-g]chromen]-8'-one
(50).
Yield: 90%; mp 165-166 °C [7]. 1H NMR (400MHz,
DMSO-d6) δ 1.93-2.09 (m, 4H), 2.34 (s, 3H), 2.83 (s, 2H),
3.08 (m, 2H), 3.23 (m, 2H), 6.14 (s, 1H), 7.42 (m, 2H), 7.52
(m, 3H), 7.73 (s, 1H), 9.35 (s, 1H), 9.62 (s, 1H), 11.36 (s,
1H). 13C NMR (100MHz, DMSO-d6) δ 8.72, 32.44, 41.00,
74.32, 112.81, 113.33, 114.50, 115.70, 119.22, 129.40,
130.11, 130.51, 145.33, 153,51, 153.62, 155.91, 160.00;
APSI MS: 391.0 (M++1). Anal. Calcd for C23H21ClN2O4: C,
64.71; H, 5.43; Cl, 8.39; N, 6.56%. Found: C, 64.90; H,
5.59; Cl, 8.50; N, 6.69%.
Notes
Acknowledgments and finances. The work was funded
by Ministry of Education and Science of Ukraine (Grant
No. 0122U001962 (22BF037-02). The authors thank all
brave defenders of Ukraine who made this publication
possible.
The authors declare no conflict of interest.
References
1. Joshi, P.P. A Review on Biological Activities of Linear
Pyranocoumarins. Int. J. Adv. Study Res. Work. 2021, 4, 20-27.
2. Vlachou, N.E.; Litinas, E.K. An overview on pyranocoumarins:
Synthesis and biological activities. Curr. Org. Chem. 2019, 23, 2679-
2721.
3. Sørensen, M.; Neilson, E.H.J.; Lindberg, B.M. Oximes: unrecogni-
zed chameleons in general and specialized plant metabolism. Mol.
Plant. 2017, 11, 95-117.
4. Surowiak, A.K.; Lochyński, S.; Strub, D.J. Unsubstituted oximes as
potential therapeutic agents. Symmetry. 2020, 12, 575.
5. Moskvina, V.S.; Turov, O.V.; Khilya, V.P.; Garazd, M.M.; Groth
U.M. Synthesis and NMR spectroscopy investigations of
functionalized 8, 8, 10-trimethyl-4-phenyl-7, 8-dihydro-2H, 6H-
pyrano [3, 2-g] chromene-2, 6-diones and their spirothiadiazole
derivatives. Monatsh Chem. 2008, 139, 1391-1396.
6. Moskvina, V.S.; Masich, D.U.; Khilya, V.P. Pyranoneoflavonoids:
Synthesis and structure. Dopov Nac Akad Nauk Ukr. 2014, 12, 122-
127 (in Ukrainian).
7. Moskvina, V.S.; Krasylov, I.V.; Khilya, V.P. Synthesis of oximes of
pyranoneoflavons and spiropyranoneoflavons. Dopov Nac Akad
Nauk Ukr. 2018, 10, 79-87 (in Ukrainian).
8. Moskvina, V.S.; Turov, O.V.; Shokol, V.P.; Khilya, V.P. Synthesis
and NMR spectroscopy investigations of functionalized
spiropyranochromenediones and their spirothiadiazole derivatives.
Ukr. Bioorg. Acta. 2021, 16, 18-22.
9. Krasylov, I.V.; Moskvina, V.S.; Shilin, S.V.; Khilya, V.P. Amino-
Acid Derivatives of Pyranocoumarins. Chem Nat Compd. 2020, 56,
832-836.
10. Tsitrina, A.A; Krasylov, I.V.; Maltsev, D.I.; Andreichenko, I.N.;
Moskvina, V.S.; Ivankov, D.N; Bulgakova, E.V.; Nesterchuk, M.;
Shashkovskaya, V.; Dashenkova, N.O.; Khilya, V.P.; Mikaelyan, A.;
Kotelevtsev, Y. Inhibition of hyaluronan secretion by novel coumarin
compounds and chitin synthesis inhibitors. Glycobiology. 2021, 31,
959-974.
I.V. Krasylov et al.
51
Синтетичний підхід до (спіро)піранокумаринів та їх оксимів
І.В. Красилов1, В.С. Москвіна1,2*, В.П. Хиля1
1 Київський національний університет імені Тараса Шевченка, Київ, Україна.
2 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна.
Резюме: В роботі досліджуються підходи до синтезу (спіро)піранокумаринів лінійної будови та іх оксимів - сполук із широким спектром
біологічної активності. Спираючись на попередні дослідження, в даній роботі розширено набір цільових сполук із диметильними та
різноманітними циклоаліфатичними групами. Розроблений підхід базується на використанні о-гідроксиацетилкумаринів в конденсації Каббе з
відповідними кетонами - в результаті отримано 16 (спіро)піранокумаринів, 12 з яких є новими сполуками. Взаємодія отриманих
(спіро)піранокумаринів з гідрохлоридом гідроксиламіну проходила селективно по екзоциклічному атому Оксигену хроман-4-ону фрагмента, та
дозволила отримати відповідні оксими з високими виходами, Оптимізація умов проведення синтезу дозволила збільшити вихід цільових
продуктів та скоротити час проведення реакції. Всі отримані похідні - (спіро)піранокумарини та їх оксими володіють корисними властивостями
для проведення подальшої структурної модифікації та створення потенційних лікарських засобів широкого спектру дії.
Ключові слова: гетероциклізація; кумарин; піранокумарин; спіропіранокумарин; оксим.
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| id | oai:ojs2.bioorganica.com.ua:article-56 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:10Z |
| publishDate | 2023 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/97/810f108d8efb322bc182536156ef2e97.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-562026-07-19T14:56:54Z Synthetic approach to spiropyranocoumarins and their oxime derivatives Синтетичний підхід до спіропіранокумаринів та їх оксимів Krasylov, Igor V. Moskvina, Viktoriia S. Khilya, Volodymyr P. heterocyclization coumarin pyranocoumarin spiropyranocoumarin oxime гетероциклізація кумарин піранокумарин спіропіранокумарин оксим This study explores the synthesis of a diverse series of linear (spiro)pyranocoumarins and their corresponding oximes, compounds known for their promising biological activities. Building on previous work, the authors expand the array of target compounds, adding structural features such as dimethyl groups and various cycloaliphatic rings. The novel synthetic procedure applied herein couples o-hydroxyacetyl coumarins with respective ketones via Kabbe condensation, yielding 16 derivatives, including 12 new compounds. A further step engages these (spiro)pyranocoumarins with hydroxylamine hydrochloride, leading to oximes, selectively at the exocyclic oxygen atom of the chroman-4-one fragment. Optimizing synthesis conditions has increased product yields and reduced reaction times. Acidic hydrolysis of select compounds introduces additional carbonyl groups and facilitates deprotection, while the subsequent reaction with hydroxylamine hydrochloride produces dual-oxime compounds. These findings contribute to the ongoing development of pyranocoumarin and oxime-based therapeutics, with potential applications in treating various diseases В роботі досліджуються підходи до синтезу (спіро)піранокумаринів лінійної будови та іх оксимів – сполук із широким спектром біологічної активності. Спираючись на попередні дослідження, в даній роботі розширено набір цільових сполук із диметильними та різноманітними циклоаліфатичними групами. Розроблений підхід базується на використанні о-гідроксиацетилкумаринів в конденсації Каббе з відповідними кетонами – в результаті отримано 16 (спіро)піранокумаринів, 12 з яких є новими сполуками. Взаємодія отриманих (спіро)піранокумаринів з гідрохлоридом гідроксиламіну проходила селективно по екзоциклічному атому Оксигену хроман-4-ону фрагмента, та дозволила отримати відповідні оксими з високими виходами, Оптимізація умов проведення синтезу дозволила збільшити вихід цільових продуктів та скоротити час проведення реакції. Всі отримані похідні – (спіро)піранокумарини та їх оксими володіють корисними властивостями для проведення подальшої структурної модифікації та створення потенційних лікарських засобів широкого спектру дії V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/56 10.15407/bioorganica2023.01.042 Ukrainica Bioorganica Acta; Vol. 18 No. 1 (2023): Ukrainica Bioorganica Acta; 42-51 Ukrainica Bioorganica Acta; Том 18 № 1 (2023): Ukrainica Bioorganica Acta; 42-51 1814-9766 1814-9758 10.15407/bioorganica2023.01 en https://bioorganica.com.ua/index.php/journal/article/view/56/69 Copyright (c) 2023 Igor V. Krasylov, Viktoriia S. Moskvina, Volodymyr P. Khilya https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | гетероциклізація кумарин піранокумарин спіропіранокумарин оксим Krasylov, Igor V. Moskvina, Viktoriia S. Khilya, Volodymyr P. Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title | Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title_alt | Synthetic approach to spiropyranocoumarins and their oxime derivatives |
| title_full | Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title_fullStr | Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title_full_unstemmed | Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title_short | Синтетичний підхід до спіропіранокумаринів та їх оксимів |
| title_sort | синтетичний підхід до спіропіранокумаринів та їх оксимів |
| topic | гетероциклізація кумарин піранокумарин спіропіранокумарин оксим |
| topic_facet | heterocyclization coumarin pyranocoumarin spiropyranocoumarin oxime гетероциклізація кумарин піранокумарин спіропіранокумарин оксим |
| url | https://bioorganica.com.ua/index.php/journal/article/view/56 |
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