Modified coumarins. 11. Synthesis and biological activity of mannich bases of substituted 2,3-dihydrocyclopenta[c]chromen-4-ones

Article abstract of DOI:10.1023/B:CONC.0000003410.74701.dc

Mannich bases containing the dialkylaminomethyl group in the 6- and 8-positions of 2,3-dihydrocyclopenta[c]chromen-4-ones were prepared by condensation of 7- and 9-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-ones with substituted 1,1-diaminomethanes. The effects of 8-chloro-7-hydroxy-6-(l- pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one and 8-chloro-7-hydroxy-6-(morpholinomethyl)-2,3-dihydrocyclopenta[c]chromen-4-one on the central and peripheral nervous system were defined and enable the presence of tranquilizing and neuroleptic properties to be predicted.

Full text of DOI:10.1023/B:CONC.0000003410.74701.dc

Chemistry of Natural Compounds, Vol. 39, No. 4, 2003
MODIFIED COUMARINS. 11. SYNTHESIS AND BIOLOGICAL
ACTIVITY OF MANNICH BASES OF SUBSTITUTED
2,3-DIHYDROCYCLOPENTA[c]CHROMEN-4-ONES
1
2
Ya. L. Garazd, T. N. Panteleimonova,
UDC 547.814.5
3
1
M. M. Garazd, and V. P. Khilya
Mannich bases containing the dialkylaminomethyl group in the 6- and 8-positions of 2,3-di-
hydrocyclopenta[c]chromen-4-ones were prepared by condensation of 7- and 9-hydroxy-2,3-
dihydrocyclopenta[c]chromen-4-ones with substituted 1,1-diaminomethanes. The effects of 8-chloro-7-
hydroxy-6-(1-pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one and 8-chloro-7-hydroxy-6-
(morpholinomethyl)-2,3-dihydrocyclopenta[c]chromen-4-one on the central and peripheral nervous system
were defined and enable the presence of tranquilizing and neuroleptic properties to be predicted.
Key words: coumarins, 2,3-dihydrocyclopenta[c]chromen-4-one, Mannich reaction, synthesis.
Natural coumarinsandtheir syntheticanalogsprovidea platformfor creatingnewpharmacologicallyactivecompounds
owing to their high biological activity. The Mannich reaction is one method of chemical modification that introduces into a
molecule a pharmacophoric base that renders the molecule water-soluble when converted to the ammonium salt. According
to the literature, most aminomethylated coumarin derivatives are central-nervous-system stimulants, barbiturate antagonists,
anticonvulsants, analgesics, antipyretics, and anti-inflammatory agents [1, 2].
In continuation of research on the synthesis and properties of Mannich bases [3, 4], we prepared and performed a
preliminary pharmacologic screening of aminomethyl derivatives of 7-hydroxy- and 9-hydroxy-2,3-
dihydrocyclopenta[c]chromen-4-ones.
Hydroxycoumarins 1-4 were necessary for further conversions and were prepared by Pechmann condensation of
polyphenols(resorcinol, 2-methylresorcinol,4-chlororesorcinol, orcine)andethyl-2-oxocyclopentanecarboxylatein thepresence
of H SO (conc.).
2
4
Classical conditions of the Mannich reaction for hydroxycompounds, upon which the benzopyran skeleton is based,
include reaction of the substrate, amine, and formaldehyde in alcohol with prolonged heating [5]. In our opinion, a more
convenient method involves introduction of the aminomethyl group into the benzopyran system by using substituted
1
,1-diaminomethanes [3, 4] because this reaction typically has a fast rate and lacks side products [6, 7].
The position ortho to the hydroxyl is known to be the most preferred for attack under Mannich-reaction conditions for
all phenolic derivatives. This is explained bythe reaction mechanism, according to which a H-bond is first formed between the
Mannich reagent and substrate, after which the o-position is attacked [5].
The C-aminomethylation reaction was carried out by refluxing hydroxycoumarins with substituted 1,1-di-
aminomethanes in absolute dioxane. The aminomethyl group enters the 6-position of the 2,3-dihydrocyclopenta[c]chromen-4-
one upon reacting with coumarins 1 and 2; the 8-position, with coumarins 3 and 4. This is consistent with the PMR
spectroscopy data.
1
) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64; 2) Institute of
Gerontology, Academy of Medical Sciences of Ukraine, 03114, Kiev, ul. Vyshgorodskaya, 67; 3) Institute of Bioorganic and
Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Kiev, ul. Murmanskaya, 1, e-mail: gmm@i.com.ua.
Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 264-269, July-August, 2003. Original article submitted July 31,
2
003.
©
0
009-3130/03/3904-0330$25.00 2003 Plenum Publishing Corporation
3
30

R
N
1
X
R2
N
R2
N
N
R
2
X
X
HO
R
O
O
O
O
HO
R
O
O
N
N
HO
R
O
O
R
1
R
1
5
- 13
1, 2
14 - 20
R
2
R
2
Me
Me
Me
X
X
N
N
HO
O
O
HO
N
O
HO
N
O
O
N
N
R
1
R
1
R
1
R
2
2
1 - 25
3
26
R
R
2
2
N
N
X
X
Me
O
O
Me
O
O
Me
N
O
R1
R
1
N
N
N
X
OH
OH
OH
2
R
R
1
2
7 - 30
4
31 - 34
1
: R = H; 2: R = Cl; 5: R = H, R = R =CH ; 6: R = Cl, R = R = CH ; 7: R = H, R = R = CH CH ;
1 2 3 1 2 3 1 2 2 3
8
1
1
1
2
2
3
: R = Cl, R = R = CH CH ; 9: R = H, R R = (CH ) ; 10: R = Cl, R R = (CH ) ;
1 2 2 3 1 2 4 1 2 2 4
2
1: R = Cl, R R = CH CH(CH )CH CH ; 12: R = H, R R = CH(CH CH )CH CH CH CH ;
1
2
2
3
2
2
1
2
2
3
2
2
2
2
3: R = Cl, R R = CH(CH CH )CH CH CH CH ; 14: R = H, X = CH ; 15: R = Cl, X = CH ;
1
2
2
3
2
2
2
2
2
2
6: R = Cl, X = CH(CH ); 17: R = H, X = O; 18: R = Cl, X = O; 19: R = H, X = NCH ;
3
3
0: R = Cl, X = NCH ; 21, 27: R = R = CH ; 22, 28: R = R = CH CH ; 23, 29: R R = (CH ) ;
3
1
2
3
1
2
2
3
1
2
2 4
4, 30: R R = CH CH(CH )CH CH ; 25: R R = CH(CH CH )CH CH CH CH ;
1
2
2
3
2
2
1
2
2
3
2
2
2
2
1: X = CH ; 32: X = CH(CH ); 33: X = O; 34: X = NCH
3
2
3
According to the experimental results, 7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (1) is the most reactive
substrate toward aminomethylation. The reaction occurs over 0.5-1 h. A longer heating period of 2-4 h is necessary if 2 is used.
The fact that an even longer period (5-10 h) is needed to carry out the Mannich reaction with 3, in our opinion, proves that the
8
8
-position of 2,3-dihydrocyclopenta[c]chromen-4-one is rather unreactive toward aminomethylation. The reactivity of the
-position increases significantly upon introducing a 9-hydroxy because the reaction with 9-hydroxy-7-methyl-2,3-
dihydrocyclopenta[c]chromen-4-one (4) is complete after heating for 1-3 h.
Aminals of dimethylamine (5, 6, 21, 27), diethylamine (7, 8, 22, 28), pyrrolidine (9, 10, 23, 29), piperidine (14, 15,
2
6, 31), 2-ethylpiperidine (12, 13, 25), 3-methylpiperidine (11, 24, 30), 4-methylpiperidine (16, 32), morpholine (17, 18, 33),
and 1-methylpiperazine (19, 20, 34) were used in the Mannich reaction. Bis(dimethylamino)methane exhibited the highest
reactivity of the 1,1-diaminomethanes. Use of the other aminals required longer heating.
The structures of the resulting Mannich bases were confirmed byelemental analyses and PMRspectroscopy. The PMR
spectra of 5-20, which contain a dialkylaminomethyl group in the 6-position, lack signals in the range 6.9-7.0 ppm for the H-6
proton of the 2,3-dihydrocyclopenta[c]chromen-4-one. As a result of the lack of coupling with H-6, the PMR spectrum in the
range of the aromatic protons is simplified. The H-8 and H-9 positions of 5, 7, 9, 12, 14, 17, and 19 resonate as doublets with
spin—spin coupling constants of 8.7-8.8 Hz at 6.70-6.76 and 7.21-7.26 ppm, respectively. For the 8-chloroderivatives 6, 8, 10,
11, 13, 15, 16, 18, and 20, H-9 resonates at 7.32-7.36 ppm as a 1H singlet. The analogous trend is noted for the
8
-dialkylaminomethyl derivatives 21-34. Proton H-9 in PMR spectra of Mannich bases 21-26 appears as a singlet at 6.89-
6
.91 ppm; for 9-hydroxy-7-methyl derivatives 27-34, H-6 resonates as a singlet at 6.61-6.65 ppm.
331

TABLE 1. Neurotropic Effects of 18 in Animal Tests
Rectal temperature with apomorphine, C
Compound
Hexenal sleep, min
Extent of nicotine
cramps, ball
initial
after 90 min
latent period
duration
Control
37.1±0.1
37.9±0.3
33.4±0.5
32.7±0.6
3.3±0.4
2.4±0.3
3.6±0.7
2.0±0.3
35.0±2.3
51.0±6.8
18
The PMR spectra of the prepared Mannich bases also contains 2H signals for the methylene and signals typical of
dialkylamine substituents. The methylene group of the 6-dialkylaminomethyl derivatives 5-11 and 14-20 appears as a singlet
at 4.04-4.26 ppm; for Mannich bases 21-23 and 26-34, which contain an 8-dialkylaminomethyl, at stronger field of 3.68-
3
.88 ppm.
It should be noted that the methylene protons in 12, 13, 24, and 25 are diastereotopic and appear as two doublets with
spin—spin coupling constant 15.0-15.6 Hz. The hydroxyl protons 7-OH and 9-OH resonate at weak field (8.60-10.50 ppm)
because they are involved in the formation of stable intramolecular H-bonds to the N atom of the dialkylaminomethyl group.
The toxicity and biological activities of 10, 18, and 29 were studied in animal (mice, rats) experiments. It has been
found that the average lethal doses (LD ) of these compounds administered orally to mice are less than 5000 mg/kg, which
5
0
corresponds to class IV toxicity (mildly toxic compounds).
Pharmacological screening has shown that 10 and 18 exhibit distinct neurotropic activity. Thus, single administration
of 10 at doses of 200 and 400 mg/kg reduced the spontaneous motor activity, (elicited adynamia), weakened the reaction to
forced body positioning, and elicited hypotonicity of skeletal muscle and an inadequate reaction to stimulation of ear and eye
iris. Compound18increasedstatisticallysignificantlyapomorphinehypothermia, potentiatedtheactivityofsoporificsubstances
(
(
increasedby46%theduration ofhexenalsleep), andreducedtheneuromuscular thresholdas evaluated bynicotine hyperkinesis
Table 1). Compound 29 at the studied doses did not affect the central nervous system.
Thus, the observed effects confirm that 10 and 18 have an influence on the central and peripheral nervous systems and
can predict the presence of tranquilizing and neuroleptic properties. These compounds may be promising for further study as
potential medicinal preparations.
EXPERIMENTAL
The course of the reactions and the purity of the products were monitored using TLC on Merck 60 F254 plates. The
eluent was CHCl :CH OH (9:1) and hexane:ethylacetate (7:3). Melting points were determined on a Kofler block. IR and UV
3
3
spectra were measured on a Nicolet FTIR Nexus 475 spectrometer and a Specord M40 spectrophotometer, respectively. PMR
spectra were recorded on Varian VXR-300 and Varian Mercury-400 spectrometers at 300 and 400 MHz, respectively, relative
to TMS (internal standard). Elemental analyses of all compounds agreed with those calculated.
Hydroxycoumarins 1, 3, and 4 were prepared as before [8].
8
-Chloro-7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (2). A cooled (0°C) solution of 4-chlororesorcinol
28.9 g, 0.2 mol) and ethyl-2-oxocyclopentacarboxylate (29 mL, 0.2 mol) in absolute ethanol (50 mL) was vigorously stirred,
cooled, and treated dropwise with H SO (conc., 20 mL). The reaction mixture was stirred until thickened and then left
(
2
4
overnight at room temperature. The mixture was poured into icewater (500 mL). The resulting precipitate was filtered off and
-1
crystallized from acetonitrile. Yield 73%, C H ClO , mp 255-256°C (lit. 245-247°C [9]). IR spectrum (KBr, cm ): 3168,
1
2
11
3
1
676, 1636, 1600, 1568, 1408, 1256, 1212, 1160, 1080, 952, 848. UV (EtOH, λmax, nm, log ε): 206 (4.71), 221 (4.25), 327
(4.29).
PMR spectrum (400 MHz, DMSO-d , δ, ppm): 2.15 (2H, m, CH -2), 2.76 (2H, m, CH -1), 2.95 (2H, m, CH -3), 6.90
6
2
2
2
(
1H, s, H-6), 7.47 (1H, s, H-9), 10.99 (1H, br.s, OH-7).
General Method for Synthesizing Mannich Bases 5-34. A solution of 1-4 (4 mmol) in absolute dioxane (30 mL)
was treated with the appropriate substituted 1,1-diaminomethane (5 mmol). The reaction mixture was stored at 100°C for
.5-10 h (completion of the reaction determined using TLC). After the reaction was complete the solvent was removed in
vacuum. The solid or oily residue was crystallized from hexane:propan-2-ol (3:1).
0
3
32

6
-[(Dimethylamino)methyl]-7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (5), yield 87%, C H NO ,
15 17 3
-1
mp 158-159°C. IR spectrum (ν, cm ): 3424, 2964, 1720, 1664, 1612, 1504, 1440, 1388, 1356, 1292, 1252, 1052, 1020, 972.
UV (EtOH, λmax, nm, log ε): 206 (4.51), 220 (4.10), 335 (4.17).
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.18 (2H, m, CH -2), 2.40 [6H, s, N(CH ) ], 2.89 (2H, m, CH -1),
3
2
3 2
2
3
.03 (2H, m, CH -3), 4.04 (2H, s, CH -6), 6.76 (1H, d, J = 8.7, H-8), 7.26 (1H, d, J = 8.7, H-9), 10.20 (1H, s, OH-7).
2 2
8
-Chloro-6-[(dimethylamino)methyl]-7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (6), yield 91%,
-1
C H ClNO , mp 185-186°C. IR spectrum (ν, cm ): 3420, 2962, 1700, 1596, 1548, 1436, 1392, 1308, 1264, 1148, 1068,
15
16
3
1
024, 976. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.52), 241 (4.04), 370 (4.31).
PMR (400 MHz, CDCl , δ, ppm): 2.19 (2H, m, CH -2), 2.42 [6H, s, N(CH ) ], 2.88 (2H, m, CH -1), 3.00 (2H, m,
3
2
3 2
2
CH -3), 4.08 (2H, s, CH -6), 7.35 (1H, s, H-9), 9.57 (1H, s, OH-7).
2
2
6
-[(Diethylamino)methyl]-7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (7), yield76%, C H NO , mp116-
17 21 3
-1
1
17°C. IR spectrum (ν, cm ): 3424, 2976, 1716, 1656, 1608, 1500, 1460, 1416, 1388, 1364, 1276, 1196, 1064. UV spectrum
(EtOH, λmax, nm, log ε): 207 (4.55), 227 (4.05), 331 (4.07).
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.15 (6H, t, J = 7.2, two CH -2′), 2.18 (2H, m, CH -2), 2.69 (4H,
3
3
2
q, J = 7.2, two CH -1′), 2.88 (2H, m, CH -1), 3.03 (2H, m, CH -3), 4.13 (2H, s, CH -6), 6.73 (1H, d, J = 8.7, H-8), 7.23 (1H,
2
2
2
2
d, J = 8.7, H-9), 8.60 (1H, s, OH-3).
8
-Chloro-6-[(diethylamino)methyl]-7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4-one (8), yield 96%,
-1
C H ClNO , mp 191-192°C. IR spectrum (ν, cm ): 3428, 2976, 1716, 1656, 1600, 1392, 1308, 1148, 1068, 924.
17
20
3
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.54), 240 (4.08), 366 (4.23).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.19 (6H, t, J = 7.2, two CH -2′), 2.18 (2H, m, CH -2), 2.76 (4H,
3
3
2
q, J = 7.2, two CH -1′), 2.87 (2H, m, CH -1), 2.99 (2H, m, CH -3), 4.18 (2H, s, CH -6), 7.33 (1H, s, H-9), 9.65 (1H, s, OH-7).
2
2
2
2
7
-Hydroxy-6-(1-pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (9), yield64%, C H NO , mp155-
17 19 3
-1
1
56°C. IR spectrum (ν, cm ): 3448, 2952, 1720, 1664, 1608, 1500, 1436, 1388, 1288, 1052. UV spectrum (EtOH, λmax, nm,
log ε): 206 (4.74), 225 (4.38), 328 (4.24).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.89 (4H, m, CH -3′, CH -4′), 2.17 (2H, m, CH -2), 2.74 (6H, m,
3
2
2
2
CH -7, CH -2′, CH -5′), 2.88 (2H, m, CH -1), 3.02 (2H, m, CH -3), 4.20 (2H, s, CH -6), 6.74 (1H, d, J = 8.8, H-8), 7.24 (1H,
2
2
2
2
2
2
d, J = 8.8, H-9), 9.82 (1H, s, OH-7).
-Chloro-7-hydroxy-6-(1-pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (10), yield 84%,
8
-1
C H ClNO , mp 202-203°C. IR spectrum (ν, cm ): 3400, 2964, 1716, 1656, 1592, 1500, 1476, 1432, 1404, 1348, 1164.
17
18
3
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.61), 239 (4.20), 370 (4.44).
PMR spectrum (400 MHz, CDCl , δ, ppm): 1.93 (4H, m, CH -3′, CH -4′), 2.18 (2H, m, CH -2), 2.82 (6H, m, CH -7,
3
2
2
2
2
CH -2′, CH -5′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3), 4.26 (2H, s, CH -6), 7.34 (1H, s, H-9), 9.50 (1H, s, OH-7).
2
2
2
2
2
8
-Chloro-7-hydroxy-6-[(3-methylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (11), yield 88%,
-1
C H ClNO , mp 183-184°C. IR spectrum (ν, cm ): 3428, 2944, 1724, 1656, 1600, 1484, 1416, 1388, 1308, 1068, 976.
19
22
3
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.59), 242 (4.07), 364 (4.24).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.90 (3H, t, J = 6.4, CH -3′), 0.95 (1H, m, CH -4′α), 1.64-1.85 (5H,
3
3
2
m, H-3′, CH -5′, CH -4′β, CH -2′α, CH -6′α), 2.18 (2H, m, CH -2), 2.87 (2H, m, CH -1), 2.93 (2H, m, CH -2′β, CH -6′β),
2
2
2
2
2
2
2
2
2
.99 (2H, m, CH -3), 4.08 (2H, s, CH -6), 7.33 (1H, s, H-9), 9.35 (1H, s, OH-7).
2 2
7
-Hydroxy-6-[(2-ethylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (12), yield 69%, C H NO ,
20 25 3
-1
mp 96-97°C. IR spectrum (ν, cm ): 3400, 2936, 1720, 1664, 1608, 1500, 1384, 1284, 1052, 922. UV spectrum (EtOH, λmax,
nm, log ε): 207 (4.56), 227 (4.08), 335 (4.15).
PMR (400 MHz, CDCl , δ, ppm, J/Hz): 0.96 (3H, t, J = 7.2, CH -2′′), 1.45-1.85 (9H, m, CH -3′, CH -4′, CH -5′,
3
3
2
2
2
CH -6′α, CH -1′′, 2.17 (2H, m, CH -2), 2.30 (1H, m, H-2′), 2.87 (2H, m, CH -1), 3.02 (2H, m, CH -3), 3.08 (1H, m, CH -6′β),
2
2
2
2
2
2
3
.98 (1H, d, J = 15.6, CH -6α), 4.35 (1H, d, J = 15.6, CH -6β), 6.70 (1H, d, J = 8.8, H-2), 7.21 (1H, d, J = 8.8, H-1), 9.40 (1H,
2 2
s, OH-7).
8
-Chloro-7-hydroxy-6-[(2-ethylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (13), yield 83%,
-1
C H ClNO , mp 194-195°C. IR spectrum (ν, cm ): 3436, 2940, 1716, 1656, 1596, 1524, 1476, 1384, 1296, 1100, 1044.
20
24
3
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.64), 240 (4.09), 358 (4.16).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.95 (3H, t, J = 7.2, CH -2′′), 1.45-1.85 (9H, m, CH -3′, CH -4′,
3
3
2
2
CH -5′, CH -6′α, CH -1′′), 2.17 (2H, m, CH -2), 2.30 (1H, m, H-2′), 2.86 (2H, m, CH -1), 2.99 (2H, m, CH -3), 3.05 (1H, m,
2
2
2
2
2
2
333

CH -6′β), 4.02 (1H, d, J = 15.6, CH -6α), 4.38 (1H, d, J = 15.6, CH -6β), 7.32 (1H, s, H-9), 9.30 (1H, s, OH-7).
2
2
2
7
-Hydroxy-6-(piperidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (14), yield 68%, C H NO , mp159-
18 21 3
-1
1
60°C. IR spectrum (ν, cm ): 3420, 2920, 1720, 1668, 1608, 1500, 1380, 1348, 1292, 1152, 1052, 960. UV spectrum (EtOH,
λmax, nm, log ε): 207 (4.49), 226 (4.05), 335 (4.12).
PMRspectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.66 (6H, m, CH -3′, CH -4′, CH -5′), 2.17 (4H, m, CH -2, CH -2′α,
3
2
2
2
2
2
CH -6′α), 2.80-2.90 (2H, m, CH -2′β, CH -6′β), 2.86 (2H, m, CH -1), 3.01 (2H, m, CH -3), 4.06 (2H, s, CH -6), 6.72 (1H,
2
2
2
2
2
2
d, J = 8.8, H-8), 7.24 (1H, d, J = 8.8, H-9), 10.14 (1H, s, OH-7).
-Chloro-7-hydroxy-6-(piperidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (15), yield89%, C H ClNO ,
8
18
20
3
-1
mp 203-204°C. IR spectrum (ν, cm ): 3400, 2936, 1720, 1660, 1600, 1384, 1308, 1152, 1064, 968. UV spectrum (EtOH,
λmax, nm, log ε): 212 (4.63), 239 (4.17), 366 (4.31).
PMR spectrum (400 MHz, CDCl , δ, ppm): 1.71 (6H, m, CH -3′, CH -4′, CH -5′), 2.18 (2H, m, CH -2), 2.20-2.30
3
2
2
2
2
(
2H, m, CH -2′α, CH -6′α), 2.80-2.90 (2H, m, CH -2′β, CH -6′β), 2.87 (2H, m, CH -1), 2.99 (2H, m, CH -3), 4.09 (2H, s,
2 2 2 2 2 2
CH -6), 7.33 (1H, s, H-9), 9.25 (1H, s, OH-7).
2
8
-Chloro-7-hydroxy-6-[(4-methylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (16), yield 86%,
-1
C H ClNO , mp 173-174°C. IR spectrum (ν, cm ): 3444, 2932, 1720, 1656, 1596, 1384, 1340, 1308, 1148, 1064, 968.
19
22
3
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.59), 241 (4.09), 366 (4.31).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.95 (3H, t, J = 6.4, CH -4′), 1.38 (2H, m, CH -3′α, CH -5′α), 1.49
3
3
2
2
(
1H, m, H-4′), 1.73 (2H, m, CH -3′β, CH -5′β), 2.18 (2H, m, CH -2), 2.31 (2H, m, CH -2′α, CH -6′α), 2.87 (2H, m, CH -1),
2 2 2 2 2 2
2
.99 (2H, m, CH -3), 3.05 (2H, m, CH -2′β, CH -6′β), 4.10 (2H, s, CH -6), 7.33 (1H, s, H-9), 9.50 (1H, s, OH-7).
2 2 2 2
7
-Hydroxy-6-(morpholinomethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (17), yield60%,C H NO , mp160-
17 19 4
-1
1
61°C. IRspectrum (ν, cm ): 3432, 2952, 1720, 1668, 1604, 1500, 1464, 1416, 1384, 1276, 1116, 1052. UV spectrum (EtOH,
λmax, nm, log ε): 206 (4.45), 225 (4.02), 328 (4.10).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 2.18 (2H, m, CH -2), 2.65 (4H, m, CH -2′, CH -6′), 2.88 (2H, m,
3
2
2
2
CH -1), 3.03 (2H, m, CH -3), 3.78 (4H, m, CH -3′, CH -5′), 4.08 (2H, s, CH -6), 6.76 (1H, d, J = 8.8, H-8), 7.26 (1H, d,
2
2
2
2
2
J = 8.8, H-9), 10.50 (1H, s, OH-7).
8
-Chloro-7-hydroxy-6-(morpholinomethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (18), yield 84%,
-1
C H ClNO , mp 221-222°C. IR spectrum (ν, cm ): 3396, 2964, 1712, 1660, 1600, 1464, 1412, 1388, 1308, 1116, 1072,
17
18
4
9
92. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.59), 238 (4.11), 359 (4.15).
PMR spectrum (400 MHz, CDCl , δ, ppm): 2.20 (2H, m, CH -2), 2.68 (4H, m, CH -2′, CH -6′), 2.89 (2H, m, CH -1),
3
2
2
2
2
3
.01 (2H, m, CH -3), 3.80 (4H, m, CH -3′, CH -5′), 4.11 (2H, s, CH -6), 7.36 (1H, s, H-9), 10.40 (1H, s, OH-7).
2
2
2
2
7
-Hydroxy-6-[(4-methylpiperazino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (19), yield82%, C H N O ,
18 22 2 3
-1
mp 185-186°C. IR spectrum (ν, cm ): 3426, 2960, 1714, 1661, 1600, 1462, 1426, 1388, 1305, 1068, 1008, 988. UV spectrum
(EtOH, λmax, nm, log ε): 208 (4.46), 226 (4.08), 335 (4.14).
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.18 (2H, m, CH -2), 2.32 (3H, s, NCH ), 2.40-2.85 (8H, m, CH -2′,
3
2
3
2
CH -3′, CH -5′, CH -6′), 2.89 (2H, m, CH -1), 3.03 (2H, m, CH -3), 4.11 (2H, s, CH -6), 6.75 (1H, d, J = 8.7, H-8), 7.26 (1H,
2
2
2
2
2
2
d, J = 8.7, H-9), 8.60 (1H, s, OH-7).
-Chloro-7-hydroxy-6-[(4-methylpiperazino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (20), yield 92%,
8
-1
C H ClN O , mp 202-203°C. IR spectrum (ν, cm ): 3396, 2956, 1724, 1664, 1600, 1460, 1436, 1388, 1300, 1148, 1068,
18
21
2 4
1
008, 988. UV spectrum (EtOH, λmax, nm, log ε): 211 (4.49), 231 (4.11), 335 (4.04).
PMR spectrum (400 MHz, CDCl , δ, ppm): 2.18 (2H, m, CH -2), 2.32 (3H, s, NCH ), 2.40-2.80 (8H, m, CH -2′,
3
2
3
2
CH -3′, CH -5′, CH -6′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3), 4.11 (2H, s, CH -6), 7.34 (1H, s, H-9), 9.60 (1H, s, OH-7).
2
2
2
2
2
2
8
-[(Dimethylamino)methyl]-7-hydroxy-6-methyl-2,3-dihydrocyclopenta[c]chromen-4-one (21), yield 86%,
-1
C H NO , mp 175-176°C. IR spectrum (ν, cm ): 3400, 2924, 1712, 1656, 1616, 1464, 1400, 1260, 1100, 1032, 984.
16
19
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.56), 229 (4.15), 333 (4.26).
PMR spectrum (300 MHz, CDCl , δ, ppm): 2.17 (2H, m, CH -2), 2.32 (3H, s, CH -6), 2.36 [6H, s, N(CH ) ], 2.87
3
2
3
3 2
(
2H, m, CH -1), 2.99 (2H, m, CH -3), 3.70 (2H, s, CH -8), 6.90 (1H, s, H-9), 10.19 (1H, s, OH-7).
2 2 2
8
-[(Diethylamino)methyl]-7-hydroxy-6-methyl-2,3-dihydrocyclopenta[c]chromen-4-one (22), yield 64%,
-1
C H NO , mp 188-189°C. IR spectrum (ν, cm ): 3444, 2964, 1712, 1660, 1616, 1460, 1404, 1324, 1244, 1104, 1052, 992.
18
23
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.76), 230 (4.28), 335 (4.38).
3
34

PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.13 (6H, t, J = 7.2, two CH -2′), 2.17 (2H, m, CH -2), 2.31 (3H,
3
3
2
s, CH -6), 2.65 (4H, q, J = 7.2, two CH -1′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3), 3.83 (2H, s, CH -8), 6.90 (1H, s, H-9),
3
2
2
2
2
8
.78 (1H, s, OH-7).
7
-Hydroxy-6-methyl-8-(1-pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (23), yield 88%,
-1
C H NO , mp 166-167°C. IR spectrum (ν, cm ): 3460, 2964, 1716, 1668, 1612, 1396, 1328, 1272, 1188, 1100, 992.
18
21
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.74), 228 (4.29), 335 (4.31).
PMR spectrum (300 MHz, CDCl , δ, ppm): 1.88 (4H, m, CH -3′, CH -4′), 2.17 (2H, m, CH -2), 2.32 (3H, s, CH -6),
3
2
2
2
3
2
.67 (4H, m, CH -2′, CH -5′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3), 3.88 (2H, s, CH -8), 6.91 (1H, s, H-9), 9.72 (1H, s,
2 2 2 2 2
OH-7).
7
-Hydroxy-6-methyl-8-[(3-methylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (24), yield 83%,
-1
C H NO , mp 199-200°C. IR spectrum (ν, cm ): 3448, 2948, 1712, 1656, 1616, 1400, 1348, 1276, 1180, 1100, 1000, 984.
20
25
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.60), 228 (4.18), 335 (4.23).
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.90 (3H, t, J = 6.0, CH -3′), 0.95 (1H, m, CH -4′α), 1.62 (1H, m,
3
3
2
H-3′), 1.70-1.82 (5H, m, CH -5′, CH -4′ , CH -2′α, CH -6′α), 2.17 (2H, m, CH -2), 2.32 (3H, s, CH -6), 2.88 (2H, m, CH -1),
2
2
2
2
2
3
2
2
.90 (2H, m, CH -2′β, CH -6′β), 3.00 (2H, m, CH -3), 3.68 (1H, d, J = 15.0, CH -8α), 3.76 (1H, d, J = 15.0, CH -8′β), 6.90
2 2 2 2 2
(
1H, s, H-9), 8.50 (1H, s, OH-7).
-Hydroxy-6-methyl-8-[(2-ethylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (25), yield 68%,
7
-1
C H NO , mp 220-221°C. IRspectrum (ν, cm ): 3400, 2940, 1708, 1660, 1612, 1532, 1400, 1276, 1100, 984. UV spectrum
21
27
3
(EtOH, λmax, nm, log ε): 211 (4.60), 227 (4.15), 335 (4.19).
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.95 (3H, t, J = 7.2, CH -2′′), 1.40-1.80 (9H, m, CH -8, CH -9,
3
3
2
2
CH -3′, CH -4′, CH -5′, CH -6′α, CH -1′′), 2.31 (3H, s, CH -6), 2.35 (1H, m, H-2′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3),
2
2
2
2
2
3
2
2
3
.08 (1H, m, CH -6′β), 3.37 (1H, d, J = 15.0, CH -4α), 4.39 (1H, d, J = 15.0, CH -4β), 6.89 (1H, s, H-9), 8.40 (1H, s, OH-7).
2 2 2
7
-Hydroxy-6-methyl-8-(piperidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (26), yield79%, C H NO ,
19 23 3
-1
mp 173-174°C. IR spectrum (ν, cm ): 3400, 2932, 1720, 1660, 1616, 1420, 1396, 1276, 1188, 1152, 1128, 984. UV spectrum
(EtOH, λmax, nm, log ε): 210 (4.56), 229 (4.09), 333 (4.16).
PMR spectrum (300 MHz, CDCl , δ, ppm): 1.66 (6H, m, CH -3′, CH -4′, CH -5′), 2.17 (2H, m, CH -2), 2.32 (3H,
3
2
2
2
2
s, CH -6), 2.60-2.70 (4H, m, CH -2′, CH -6′), 2.88 (2H, m, CH -1), 3.00 (2H, m, CH -3), 3.72 (2H, s, CH -8), 6.89 (1H, s,
3
2
2
2
2
2
H-9), 8.74 (1H, s, OH-7).
8
-[(Dimethylamino)methyl]-9-hydroxy-7-methyl-2,3-dihydrocyclopenta[c]chromen-4-one (27), yield 86%,
-1
C H NO , mp 168-169°C. IR spectrum (ν, cm ): 3432, 2960, 1716, 1660, 1616, 1520, 1460, 1404, 1384, 1144, 1072, 1016,
16
19
3
9
92. UV spectrum (EtOH, λmax, nm, log ε): 209 (4.50), 259 (3.92), 313 (4.09).
PMR spectrum (400 MHz, CDCl , δ, ppm): 2.10 (2H, m, CH -2), 2.26 (3H, s, CH -7), 2.38 [6H, s, N(CH ) ], 2.80
3
2
3
3 2
(
2H, m, CH -1), 3.36 (2H, m, CH -3), 3.68 (2H, s, CH -8), 6.61 (1H, s, H-6), 9.60 (1H, s, OH-9).
2 2 2
8
-[(Diethylamino)methyl]-9-hydroxy-7-methyl-2,3-dihydrocyclopenta[c]chromen-4-one (28), yield 72%,
-1
C H NO , mp 106-107°C. IR spectrum (ν, cm ): 3416, 2972, 1712, 1660, 1612, 1448, 1380, 1192, 1144, 1068, 984.
18
23
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.50), 260 (3.92), 311 (4.10).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.16 (6H, t, J = 7.2, two CH -2 ), 2.10 (2H, m, CH -2), 2.26 (3H,
3
3
2
s, CH -7), 2.69 (4H, q, J = 7.2, two CH -1′), 2.80 (2H, m, CH -1), 3.36 (2H, m, CH -3), 3.70 (2H, s, CH -8), 6.62 (1H, s, H-6),
3
2
2
2
2
9
.55 (1H, s, OH-9).
9
-Hydroxy-7-methyl-8-(1-pyrrolidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (29), yield 87%,
-1
C H NO , mp 159-160°C. IR spectrum (ν, cm ): 3416, 2964, 1716, 1660, 1616, 1456, 1416, 1376, 1324, 1144, 1068.
18
21
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.43), 260 (3.88), 313 (4.03).
PMR spectrum (400 MHz, CDCl , δ, ppm): 1.89 (4H, m, CH -3′, CH -4′), 2.11 (2H, m, CH -2), 2.27 (3H, s, CH -7),
3
2
2
2
3
2
.65 (4H, m, CH -2′, CH -5′), 2.80 (2H, m, CH -1), 3.38 (2H, m, CH -3), 3.86 (2H, s, CH -8), 6.61 (1H, s, H-6), 9.60 (1H, s,
2 2 2 2 2
OH-9).
9
-Hydroxy-7-methyl-8-[(3-methylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (30), yield 92%,
-1
C H NO , mp 141-142°C. IR spectrum (ν, cm ): 3456, 2932, 1720, 1668, 1620, 1456, 1384, 1144, 1068, 976. UV spectrum
20
25
3
(EtOH, λmax, nm, log ε): 210 (4.52), 260 (3.97), 311 (4.16).
335

PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.89 (3H, t, J = 6.4, CH -3′), 0.96 (1H, m, CH -4′α), 1.65-1.80 (5H,
3
3
2
m, H-3′, CH -5′, CH -4′β, CH -2′α, CH -6′α), 2.11 (2H, m, CH -2), 2.26 (3H, s, CH -7), 2.80 (2H, m, CH -1), 2.92 (2H, m,
2
2
2
2
2
3
2
CH -2′β, CH -6′β), 3.37 (2H, m, CH -3), 3.68 (2H, s, CH -8), 6.61 (1H, s, H-6), 9.50 (1H, s, OH-9).
2
2
2
2
9
-Hydroxy-7-methyl-8-(piperidinylmethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (31), yield89%, C H NO ,
19 23 3
-1
mp 189-190°C. IR spectrum (ν, cm ): 3400, 2936, 1720, 1656, 1620, 1536, 1480, 1452, 1400, 1372, 1176, 1080, 1040, 988.
UV spectrum (EtOH, λmax, nm, log ε): 209 (4.69), 260 (4.11), 313 (4.27).
PMR spectrum (400 MHz, CDCl , δ, ppm): 1.66 (6H, m, CH -3′, CH -4′, CH -5′), 2.11 (2H, m, CH -2), 2.26 (3H,
3
2
2
2
2
s, CH -7), 2.80 (2H, m, CH -1), 2.90-3.10 (4H, m, CH -2′, CH -5′), 3.38 (2H, m, CH -3), 3.69 (2H, s, CH -8), 6.61 (1H, s,
3
2
2
2
2
2
H-6), 9.50 (1H, s, OH-9).
9
-Hydroxy-7-methyl-8-[(4-methylpiperidino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (32), yield 89%,
-1
C H NO , mp 173-174°C. IR spectrum (ν, cm ): 3392, 2948, 1724, 1656, 1620, 1456, 1400, 1384, 1168, 1068.
20
25
3
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.45), 260 (3.86), 313 (4.03).
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.96 (3H, t, J = 6.4, CH -4′), 1.30 (2H, m, CH -3′α, CH -5′α), 1.50
3
3
2
2
(
1H, m, H-4′), 1.70 (2H, m, CH -3′β, CH -5′β), 2.11 (4H, m, CH -2, CH -2′α, CH -6′α), 2.26 (3H, s, CH -3), 2.80 (2H, m,
2 2 2 2 2 3
CH -1), 2.97 (2H, m, CH -2′β, CH -6′β), 3.38 (2H, m, CH -3), 3.70 (2H, s, CH -8), 6.61 (1H, s, H-6), 9.50 (1H, s, OH-9).
2
2
2
2
2
9
-Hydroxy-7-methyl-8-(morpholinomethyl)-2,3-dihydrocyclopenta[c]chromen-4-one (33), yield92%, C H NO ,
18 21 4
-1
mp 159-160°C. IR spectrum (ν, cm ): 3428, 2848, 1708, 1660, 1620, 1460, 1416, 1384, 1348, 1272, 1144, 1116, 1072, 1000.
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.56), 259 (3.97), 311 (4.17).
PMR spectrum (400 MHz, CDCl , δ, ppm): 2.12 (4H, m, CH -2), 2.29 (3H, s, CH -3), 2.50-2.65 (4H, m, CH -2′,
3
2
3
2
CH -6′), 2.80 (2H, m, CH -1), 3.37 (2H, m, CH -3), 3.70-3.80 (4H, m, CH -3′, CH -5′), 3.74 (2H, s, CH -8), 6.65 (1H, s, H-6),
2
2
2
2
2
2
9
.30 (1H, s, OH-9).
9
-Hydroxy-7-methyl-8-[(4-methylpiperazino)methyl]-2,3-dihydrocyclopenta[c]chromen-4-one (34), yield 84%,
-1
C H N O , mp 189-190°C. IRspectrum (ν, cm ): 3436, 2936, 1716, 1660, 1564, 1456, 1416, 1352, 1284, 1160, 1140, 1068,
1
9 24 2 3
1
008. UV spectrum (EtOH, λmax, nm, log ε): 209 (4.56), 260 (3.96), 311 (4.16).
PMR spectrum (400 MHz, CDCl , δ, ppm): 2.11 (4H, m, CH -2), 2.27 (3H, s, CH -3), 2.32 (3H, s, NCH ), 2.40-2.80
3
2
3
3
(
4H, m, CH -2′, CH -3′, CH -5′, CH -6′), 2.80 (2H, m, CH -1), 3.38 (2H, m, CH -3), 3.73 (2H, s, CH -8), 6.63 (1H, s, H-6),
2
2
2
2
2
2
2
9
.10 (1H, s, OH-9).
ACKNOWLEDGMENT
We thank OAO "Eximed" (Kiev, Ukraine) for assistance with the work.
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1.
2.
3.
4.
5.
6.
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8.
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3
36