Modified coumarins. 7. Synthesis and biological activity of mannich bases of substituted 7,8,9,10-tetrahydrobenzo[c]chromen-6-ones

Article abstract of DOI:10.1023/A:1022674318345

Condensation of 1- and 3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-ones with substituted 1,1-diaminomethanes produced Mannich bases containing a dialkylaminomethyl group in the 2- and 4-positions of 7, 8,9,10-tetrahydrobenzo[c]chromen-6-one. Pharmacological screening of 2-chloro-3-hydroxy-4-(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c] chromen-6-one in Wistar rats showed that it possesses low toxicity and acts as a stimulant of the central and peripheral nervous systems with indications of neuroleptic and tranquilizing activities.

Full text of DOI:10.1023/A:1022674318345

Chemistry of Natural Compounds, Vol. 38, No. 6, 2002
MODIFIED COUMARINS. 7. SYNTHESIS AND BIOLOGICAL
ACTIVITY OF MANNICH BASES OF SUBSTITUTED
7,8,9,10-TETRAHYDROBENZO[c]CHROMEN-6-ONES
Ya. L. Garazd,1 T. N. Panteleimonova,2
M. M. Garazd,3 and V. P. Khilya1
UDC 547.814.5
Condensation of 1- and 3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-ones with substituted 1,1-
diaminomethanes produced Mannich bases containing a dialkylaminomethyl group in the 2- and 4-positions
of 7,8,9,10-tetrahydrobenzo[c]chromen-6-one. Pharmacological screening of 2-chloro-3-hydroxy-4-(1-
pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one in Wistar rats showed that it possesses
low toxicity and acts as a stimulant of the central and peripheral nervous systems with indications of
neuroleptic and tranquilizing activities.
Key words: coumarins, 7,8,9,10-tetrahydrobenzo[c]chromen-6-one, Mannich reaction, synthesis.
One of the alternate routes to the production of new biologicallyactive compounds is the synthesis ofanalogs ofnatural
bioregulators in order to increase the pharmacological activity, in particular, by forming several active centers in the molecule.
An advantage of such compounds is that they have structures close to the biochemical structures of the living organism and
cause significantlyless side effects. Owing to the high biological activityof natural coumarins and their synthetic analogs, they
provide a basis for producing new pharmacologically active compounds. The Mannich reaction is one method of chemical
modification that introduces into a molecule a pharmacophoric base that can be converted to an ammonium salt and make the
molecule soluble in aqueous systems. According to the literature [1, 2], the majority of aminomethylated coumarin derivatives
act as central-nervous-system stimulants, barbiturate antagonists, anticonvulsives, analgesics, antipyretics, and anti-
inflammatory agents.
We synthesized Mannich bases based on 1-hydroxy- and 3-hydroxy-7,8,9,10-tetrahydrobenzo[ ]chromen-6-ones.
c
Hydroxycoumarins 1-4, which are necessary for further transformations, were prepared by Pechmann condensation of
polyphenols (resorcinol, 2-methylresorcinol, 4-chlororesorcinol, orcin) and ethyl-2-oxocyclohexanecarboxylate in the presence
of conc. H SO .
2
4
The reaction of a substrate, amine, and formaldehyde in alcohol with prolonged heating are considered the classical
conditions for the Mannich reaction of hydroxy compounds based on the benzopyran skeleton [3]. In our opinion, a more
convenient method for introducing the aminomethyl group into the benzopyran system is the use of substituted
1,1-diaminomethanes because such reactions have fast reaction rates and few side reactions [4, 5].
It is known that the position
to a hydroxyl is the most preferred for attack under Mannich-reaction conditions
ortho
for all phenol derivatives. This is due to the reaction mechanism, according to which a H-bond is formed between the Mannich
reagent and the substrate, after which the -position is attacked [3].
o
The C-aminomethylation reaction is carried out by boiling hydroxycoumarins with substituted 1,1-diaminomethanes
in absolutedioxane. Theaminomethyl group adds tothe4-position of7,8,9,10-tetrahydrobenzo[ ]chromen-6-oneupon reaction
c
with coumarins 1 and 2. For 3 and 4, it is directed to the 2-position according to PMR spectroscopy.
1) Taras Shevchenko Kiev National University, Kiev, ul. Vladimirskaya, 64; 2) Gerontology Institute, Academy of
Medical Sciences of the Ukraine, Kiev, ul. Vyshgorodskaya, 67; 3) Institute of Bioorganic and Petroleum Chemistry, National
AcademyofSciences of the Ukraine, Kiev, ul. Murmanskaya, 1, e-mail: gmm@i.com.ua. Translated from Khimiya Prirodnykh
Soedinenii, No. 6, pp. 422-427, November-December, 2002. Original article submitted November 18, 2002.
0009-3130/02/3806-0532$27.00 ©2002 Plenum Publishing Corporation
532

R
N
1
X
R
N
R
N
2
2
R
X
X
2
N
N
N
HO
R
O
O
HO
R
O
O
HO
R
O
O
R
1
R
1
13 - 20
5 - 12
1, 2
R
R
2
2
Me
Me
Me
X
X
N
N
HO
O
O
HO
O
O
N
N
HO
O
O
R
1
R
1
N
1
N
R
R
2
21, 22
3
23 - 25
X
R
R
2
2
X
X
Me
O
O
Me
N
O
O
N
N
Me
O
O
N
N
R
1
R
1
N
X
OH
OH
OH
R
R
2
1
4
26, 27
28 - 30
1:
8:
2:
5:
6:
7:
R1 = R2 = CH2CH(CH3)CH2CH2;
R = Cl, R1 = R2 =CH(CH2CH3)CH2CH2CH2CH2;
16:
R = H; R = Cl; R = H, R1 = R2 = CH3; R = Cl, R1 = R2 = CH3; R = Cl, R1 = R2 = CH2CH3;
9:
10:
R = H, R1= R2 = (CH2)4; R = Cl, R1= R2 = (CH2)4;
11:
13:
17:
12:
R = Cl, R1 = R2 =CH2CH(CH3)CH2CH2;
14:
15:
R = H, X = CH2;
R = Cl, X = CH2;
R = H, X = CH(CH3);
R = Cl, X = CH(CH3);
R1 = R2 = CH3;
25 30
18:
19:
21, 26:
R = H, X = NCH3;
R = H, X = O;
R = Cl, X = O;
22, 27:
23 28
,
24, 29:
: X = CH2; X = CH(CH3);
R1 = R2 = (CH2)4;
,
: X = NCH3
According to the results, the most active substrate in the aminomethylation reaction is 3-hydroxy-7,8,9,10-tetrahydro-
1
6H-benzo[c]chromen-6-one ( ), the reaction of which occurs within 0.5-1 h. Longer heating for 2-4 h is needed if 2-chloro
2
derivative is used. In our opinion, the low reactivity toward aminomethylation of the 2-position of 7,8,9,10-tetrahydro-6H-
benzo[c]chromen-6-one proves that longer heating (5-10 h) is necessary to effect the Mannich reaction with the 4-methyl
3
substituted derivative . The activity of the 2-position increases significantly upon introducing a hydroxy in the 1-position
becauseheatingfor 1-3h isneededtocompletethereaction for 1-hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-
4
one ( ).
5 6 21 26
Aminals of dimethylamine ( , ,
7
8 9 22 27
13 14 23 28
), piperidine ( , , ,
,
), diethylamine ( ), pyrrolidine ( , ,
,
),
17 18
), morpholine ( , ), and
12
10 11 15 16 24 29
2-ethylpiperidine ( ), 3-methylpiperidine (
,
), 4-methylpiperidine (
,
,
,
19 20 25 30
1-methylpiperazine ( ) underwent the Mannich reaction. The most active of the 1,1-diaminomethanes was
,
,
,
bis(dimethylamino)methane. Longer heating times are required if other aminals are used.
The structures of the Mannich bases were confirmed by quantitative elemental analysis and PMR spectroscopy. The
5 20
PMR spectra of - , which contain a dialkylaminomethyl group in the 4-position, lack signals at 6.9-7.0 ppm for H-4 of
7,8,9,10-tetrahydrobenzo[c]chromen-6-one. Because H-4 does not couple, the spectrum is simplified for the aromatic protons.
5 8 10 13 15 17
Protons H-1 and H-2 of , ,
19
, and resonate as doublets with spin—spin coupling constants (SSCC) 8.8 Hz at
,
,
,
6 7 9 11 12 14 16 18 20
, and , H-1 is observed at 7.44-
7.35-7.38 and 6.72-6.75 ppm, respectively. For 2-chloro derivatives , , ,
7.48 ppm as a 1-Hsinglet. An analogous trend is noted for 2-dialkylaminomethyl derivatives
21 25
,
,
,
,
21 30
-
. Proton H-1 in PMR spectra
26 30
of Mannich bases
-
appears as a singlet at 7.00-7.03 ppm; for 1-hydroxy-3-methyl isomers
- , H-4 resonates as a singlet
5 30
at 6.57-6.58 ppm. The PMR spectra of - also contain 2H signals for the methylene and signals typical of dialkylamine
533

substituents. The methylene group of 4-dialkylaminomethyl derivatives 5-11 and 13-20 appears as a singlet at 4.01-4.23 ppm;
for 21-30, which contain the dialkylaminomethyl group in the 2-position, the methylene singlet occurs at stronger field, 3.67-
3.87 ppm. It is noteworthy that the methylene protons in 12 are diastereotopic, as a result of which they appear as two doublets
with SSCC 16.0 Hz. Hydroxyl protons OH-1 and OH-3 resonate at weak field (9.00-11.90 ppm) because they participate in
stable intramolecular H-bonds with the N atom of the dialkylaminomethyl group.
Preliminary pharmacological screening of 2-chloro-3-hydroxy-4(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-6-one (9) carried out with Wistar rats showed that it possesses low toxicity, LD50 = 2500 mg/kg. Compound
9 acts as a stimulant of the central and peripheral nervous systems with indications of neuroleptic and tranquilizing activity.
This Mannich base at a dose of 50 mg/kg increases by 65% the duration of narcotic sleep induced by hexenal and has no effect
on nicotinic hyperkinesis, i.e., possesses cholinolytic properties.
Thus,preliminarypharmacologicalscreeningshowsthatderivativesof7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
are promising for further investigations in the search for new biologically active compounds.
EXPERIMENTAL
The course ofreactions and purityofproducts were monitored byTLC on Merck60F254 plates using CHCl —CH OH
3
3
(9:1) and hexane—ethylacetate (7:3). IR and UV 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.
3-Hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (1). A cooled (0°C) solution of resorcinol (11.0 g,
0.1 mole) and ethyl-2-oxocyclohexanecarboxylate(16.0mL, 0.1mole)in ethanol (20 mL) was vigorouslystirred, cooled, treated
dropwise with conc. H SO (10 mL), stirred until thickened, and left overnight at room temperature. The mixture was poured
2
4
into icewater (250 mL). The resulting precipitate was filtered off and crystallized from propan-2-ol. Yield 16.42 g (76%),
C13H12O3, mp 205-206°C {lit. 185°C (dec.) [6], 201-202°C [7], 203-204°C [8, 9], 206-208°C [10], 210°C [11]}. IR spectrum
(KBr, cm-1): 3217, 2941, 1682, 1618, 1565, 1512, 1462, 1390, 1317, 1298, 1267, 1161, 1150, 1101, 1042, 854, 756. UV
spectrum (dioxane, λmax, nm, log ε): 219 (4.40), 291 (4.07), 319 (4.29). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz):
6
1.70 (4H, m, CH -8, CH -9), 2.35 (2H, m, CH -10), 2.66 (2H, m, CH -7), 6.65 (1H, d, J = 2.1, H-4), 6.75 (1H, dd, J = 2.1,
2
2
2
2
J = 8.7, H-2), 7.45 (1H, d, J = 8.7, H-1), 10.00 (1H, br.s, OH-3).
2-Chloro-3-hydroxy-7,8,9,10-tetrahydro-6H- benzo[c]chromen-6-one (2). Prepared analogously to 1 from
4-chlororesorcinol (14.46 g, 0.1 mole) and ethyl-2-oxocyclohexanecarboxylate (16.0 mL, 0.1 mole), yield 19.80 g (79%),
C13H11ClO3, mp 251-252°C (lig. 240-242°C [12]). IR spectrum (KBr, cm-1): 3316, 2938, 1698, 1600, 1426, 1401, 1291, 1268,
1247, 1116, 1033, 872. UV spectrum (EtOH, λmax, nm, log ε): 207 (4.72), 226 (4.39), 328 (4.26). PMR spectrum (300 MHz,
DMSO-d , δ, ppm): 1.71 (4H, m, CH -8, CH -9), 2.36 (2H, m, CH -10), 2.65 (2H, m, CH -7), 6.86 (1H, s, H-4), 7.69 (1H, s,
6
2
2
2
2
H-1), 10.00 (1H, br.s, OH-3).
3-Hydroxy-4-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (3). Prepared analogously to 1, from
2-methylresorcinol (12.41 g, 0.1 mole) and ethyl-2-oxocyclohexanecarboxylate (16.0 mL, 0.1 mole), yield 19.34 g (84%),
C14H14O3, mp 272-273°C (lit. 268°C [13], 279-281°C [14]). IR spectrum (KBr, cm-1): 3274, 2932, 1676, 1607, 1581, 1507,
1421, 1375, 1313, 1266, 1249, 1147, 1102, 805, 759. UV spectrum (EtOH, λmax, nm, log ε): 204 (4.70), 225 (4.22), 324 (4.18).
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.72 (4H, m, CH -8, CH -9), 2.16 (3H, s, CH -4), 2.39 (2H, m, CH -10),
6
2
2
3
2
2.72 (2H, m, CH -7), 6.82 (1H, d, J = 8.7, H-2), 7.34 (1H, d, J = 8.7, H-1), 10.10 (1H, br.s, OH-3).
2
1-Hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (4). Prepared analogously to 1 from orcin
monohydrate (14.22 g, 0.1 mole) and ethyl-2-oxocyclohexanecarboxylate (16.0 mL, 0.1 mole), yield 14.05 g (61%), C14H14O3,
mp 228-229°C (lit. 243-245°C [15]). IR spectrum (KBr, cm-1): 3308, 2947, 1677, 1621, 1600, 1512, 1430, 1386, 1361, 1277,
1094, 1035, 829. UV spectrum (dioxane, λmax, nm, log ε): 212 (4.60), 245 (4.04), 255 (4.02), 298 (4.26). PMR spectrum
(300 MHz, DMSO-d , δ, ppm): 1.67 (4H, m, CH -8, CH -9), 2.26 (3H, s, CH -3), 2.38 (2H, m, CH -10), 3.08 (2H, m, CH -7),
6
2
2
3
2
2
6.56 and 6.58 (2H, two s, H-2, H-4), 10.28 (1H, br.s, OH-1).
General Method for Synthesizing Mannich Bases 5-30. A solution of coumarin 1-4 (4 mmole) in absolute dioxane
(30 mL) was treated with the appropriate substituted 1,1-diaminomethane (5 mmole). The reaction mixture was held at 100°C
534

for 0.5-10 h (completion of reaction determined by TLC). After the reaction was complete, solvent was removed in vacuum.
The solid or oily product was crystallized from hexane—propan-2-ol (3:1).
4-[(Dimethylamino)methyl]-3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (5).
Yield 81%,
C16H19NO3, mp 161-162°C. IR spectrum (KBr, cm-1): 3411, 2953, 1712, 1627, 1606, 1499, 1384, 1290, 1240, 1084, 1068,
1013, 815. UV spectrum (EtOH, λmax, nm, log ε): 206 (4.84), 224 (4.39), 328 (4.33), 342 (4.22). PMR spectrum (400 MHz,
CDCl , δ, ppm, J/Hz): 1.82 (4H, m, CH -8, CH -9), 2.43 [6H, s, N(CH ) ], 2.54 (2H, m, CH -10), 2.74 (2H, m, CH -7), 4.01
3
2
2
3 2
2
2
(2H, s, CH -4), 6.75 (1H, d, J = 8.8, H-2), 7.37 (1H, d, J = 8.8, H-1), 11.10 (1H, s, OH-3).
2
2-Chloro-4-[(dimethylamino)methyl]-3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (6). Yield88%,
C16H18ClNO3, mp 155-156°C. IR spectrum (KBr, cm-1): 3393, 2944, 1708, 1623, 1598, 1477, 1390, 1358, 1300, 1246, 1103,
1056, 1015, 998, 758. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.67), 362 (4.19). PMR spectrum (400 MHz, CDCl , δ,
3
ppm): 1.81 (4H, m, CH -8, CH -9), 2.43 [6H, s, N(CH ) ], 2.54 (2H, m, CH -10), 2.70 (2H, m, CH -7), 4.05 (2H, s, CH -4),
2
2
3 2
2
2
2
7.47 (1H, s, H-1), 11.81 (1H, s, OH-3).
2-Chloro-4-[(diethylamino)methyl]-3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (7). Yield 75%,
C18H22ClNO3, mp 156-157°C. IR spectrum (KBr, cm-1): 3400, 2938, 1713, 1622, 1596, 1479, 1415, 1387, 1295, 1271, 1097,
1042, 870, 754. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.52), 358 (4.13). PMR spectrum (400 MHz, CDCl , δ, ppm,
3
J/Hz): 1.18 (6H, t, J = 7.2, two CH -2′), 1.82 (4H, m, CH -8, CH -9), 2.53 (2H, m, CH -10), 2.69 (2H, m, CH -7), 2.75 (4H,
3
2
2
2
2
q, two CH -1′), 4.16 (2H, s, CH -4), 7.45 (1H, s, H-1), 11.90 (1H, s, OH-3).
2
2
3-Hydroxy-4-(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (8). Yield81%, C18H21NO3,
mp 132-133°C. IR spectrum (KBr, cm-1): 3397, 2940, 1714, 1626, 1604, 1496, 1386, 1284, 1243, 1084, 1067, 1044, 808. UV
spectrum (dioxane, λmax, nm, log ε): 225 (4.15), 322 (4.20). PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.82 (4H, m,
3
CH -8, CH -9), 1.88 (4H, m, CH -3′, CH -4′), 2.54 (2H, m, CH -10), 2.74 (6H, m, CH -7, CH -2″, CH -5′), 4.18 (2H, s,
2
2
2
2
2
2
2
2
CH -4), 6.74 (1H, d, J = 8.8, H-2), 7.36 (1H, d, J = 8.8, H-1), 9.70 (1H, s, OH-3).
2
2-Chloro-3-hydroxy-4-(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (9). Yield 83%,
C18H20ClNO3, mp 196-197°C. IR spectrum (KBr, cm-1): 3434, 2935, 1703, 1584, 1478, 1427, 1398, 1328, 1292, 1261, 1242,
1175, 1100, 1038, 869, 753. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.64), 366 (4.26). PMR spectrum (400 MHz, CDCl ,
3
δ, ppm): 1.82 (4H, m, CH -8, CH -9), 1.92 (4H, m, CH -3′, CH -4′), 2.53 (2H, m, CH -10), 2.70 (2H, m, CH -7), 2.80 (4H,
2
2
2
2
2
2
m, CH -2″, CH -5′), 4.23 (2H, s, CH -4), 7.46 (1H, s, H-1), 9.16 (1H, s, OH-3).
2
2
2
3-Hydroxy-4-[(3-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (10). Yield 76%,
C20H25NO3, mp 156°C. IR spectrum (KBr, cm-1): 3410, 2935, 1714, 1625, 1601, 1491, 1385, 1289, 1091, 1065, 1040, 811.
UV spectrum (EtOH, λmax, nm, log ε): 204 (4.71), 226 (4.21), 320 (4.25). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz):
3
0.89 (3H, t, J = 6.0, CH -3′), 0.95 (1H, m, CH -4′α), 1.62 (1H, m, H-3′), 1.70-1.84 (9H, m, CH -8, CH -9, CH -5′, CH -4′β,
3
2
2
2
2
2
CH -2′α, CH -6′α), 2.54 (2H, m, CH -10), 2.74 (2H, m, CH -7), 2.91 (2H, m, CH -2′β, CH -6′β), 4.02 (2H, s, CH -4), 6.74
2
2
2
2
2
2
2
(1H, d, J = 8.7, H-2), 7.34 (1H, d, J = 8.7, H-1), 10.43 (1H, s, OH-3).
2-Chloro-3-hydroxy-4-[(3-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (11). Yield
80%, C20H24ClNO3, mp 183-184°C. IR spectrum (KBr, cm-1): 3405, 2932, 1715, 1622, 1597, 1478, 1415, 1385, 1294, 1101,
1049, 968, 754. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.53), 354 (4.09). PMR spectrum (400 MHz, CDCl , δ, ppm,
3
J/Hz): 0.89 (3H, t, J = 5.6, CH -3′), 0.95 (1H, m, CH -4′α), 1.68 (1H, m, H-3′), 1.73-1.85 (9H, m, CH -8, CH -9, CH -5′, CH -
3
2
2
2
2
2
4′β, CH -2′α, CH -6′α), 2.53 (2H, m, CH -10), 2.69 (2H, m, CH -7), 2.94 (2H, m, CH -2′β, CH -6′β), 4.05 (2H, s, CH -4),
2
2
2
2
2
2
2
7.45 (1H, s, H-1), 9.90 (1H, s, OH-3).
2-Chloro-3-hydroxy-4-[(2-ethylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (12). Yield
73%, C21H26ClNO3, mp 165-166°C. IR spectrum (KBr, cm-1): 3411, 2939, 1716, 1624, 1596, 1473, 1383, 1295, 1268, 1100,
1044, 967, 753. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.64), 358 (4.20). PMR spectrum (400 MHz, CDCl , δ, ppm,
3
J/Hz): 0.94 (3H, t, J = 7.6, CH -2″), 1.44-1.83 (13H, m, CH -8, CH -9, CH -3′, CH -4′, CH -5′, CH -6′α, CH -1″), 2.36 (1H,
3
2
2
2
2
2
2
2
m, H-2′), 2.52 (2H, m, CH -10), 2.69 (2H, m, CH -7), 3.08 (1H, m, CH -6′β), 4.02 (1H, d, J = 16.0, CH -4α), 4.38 (1H, d,
2
2
2
2
J = 16.0, CH -4β), 7.44 (1H, s, H-1), 10.70 (1H, s, OH-3).
2
3-Hydroxy-4-piperidinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (13). Yield76%, C19H23NO3, mp
156-157 C (lit. 170°C [16]). IR spectrum (KBr, cm-1): 3395, 2931, 1709, 1626, 1602, 1496, 1410, 1379, 1287, 1263, 1089,
1063, 1041, 989, 808, 758. UV spectrum (dioxane, λmax, nm, log ε): 221 (4.22), 322 (4.17). PMR spectrum (400 MHz, CDCl ,
3
δ, ppm, J/Hz): 1.66 (6H, m, CH -3′, CH -4′, CH -5′), 1.82 (4H, m, CH -8, CH -9), 2.10-2.20 (2H, m, CH -2′α, CH -6′α), 2.54
2
2
2
2
2
2
2
535

(2H, m, CH -10), 2.74 (2H, m, CH -7), 2.80-2.95 (2H, m, CH -2′β, CH -6′β), 4.02 (2H, s, CH -4), 6.72 (1H, d, J = 8.8, H-2),
2
2
2
2
2
7.35 (1H, d, J = 8.8, H-1), 10.80 (1H, s, OH-3).
2-Chloro-3-hydroxy-4-piperidinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (14). Yield 89%,
C19H22ClNO3, mp 195-196°C. IR spectrum (KBr, cm-1): 3404, 2943, 1711, 1622, 1597, 1478, 1384, 1339, 1294, 1266, 1098,
1046, 755. UV spectrum (EtOH, λmax, nm, log ε): 212 (4.77), 352 (4.31). PMR spectrum (400 MHz, CDCl , δ, ppm): 1.71
3
(6H, m, CH -3′, CH -4′, CH -5′), 1.81 (4H, m, CH -8, CH -9), 2.10-2.20 (2H, m, CH -2′α, CH -6′α), 2.54 (2H, m, CH -10),
2
2
2
2
2
2
2
2
2.71 (2H, m, CH -7), 2.80-2.95 (2H, m, CH -2′β, CH -6′β), 4.07 (2H, s, CH -4), 7.46 (1H, s, H-1), 11.00 (1H, s, OH-3).
2
2
2
2
3-Hydroxy-4-[(4-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (15). Yield 83%,
C20H25NO3, mp 142-143°C. IRspectrum (KBr, cm-1): 3396, 2924, 1709, 1603, 1496, 1381, 1287, 1264, 1086, 1063, 1045, 972,
808, 758. UV spectrum (EtOH, λmax, nm, log ε): 205 (4.75), 225 (4.24), 322 (4.30). PMR spectrum (400 MHz, CDCl , δ, ppm,
3
J/Hz): 0.95 (3H, t, J = 6.4, CH -4′), 1.30 (2H, m, CH -3′α, CH -5′α), 1.47 (1H, m, H-4′), 1.70 (2H, m, CH -3′β, CH -5′β), 1.82
3
2
2
2
2
(4H, m, CH -8, CH -9), 2.21 (2H, m, CH -2′α, CH -6′α), 2.54 (2H, m, CH -10), 2.74 (2H, m, CH -7), 2.98 (2H, m, CH -2′β,
2
2
2
2
2
2
2
CH -6′β), 4.03 (2H, s, CH -4), 6.72 (1H, d, J = 8.8, H-2), 7.35 (1H, d, J = 8.8, H-1), 11.15 (1H, s, OH-3).
2
2
2-Chloro-3-hydroxy-4-[(4-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (16). Yield
85%, C20H24ClNO3, mp 152-153° C. IR spectrum (KBr, cm-1): 3414, 2928, 1721, 1597, 1481, 1418, 1384, 1342, 1298, 1263,
1101, 1048, 971, 868, 754. UV spectrum (dioxane, λmax, nm, log ε): 212 (4.72), 230 (4.40), 329 (4.29). PMR spectrum
(400 MHz, CDCl , δ, ppm, J/Hz): 0.95 (3H, t, J = 6.4, CH -4′), 1.34 (2H, m, CH -3′α, CH -5′α), 1.48 (1H, m, H-4′), 1.71 (2H,
3
3
2
2
m, CH -3′β, CH -5′β), 1.82 (4H, m, CH -8, CH -9), 2.30 (2H, m, CH -2′α, CH -6′α), 2.53 (2H, m, CH -10), 2.69 (2H, m,
2
2
2
2
2
2
2
CH -7), 3.02 (2H, m, CH -2′β, CH -6′β), 4.07 (2H, s, CH -4), 7.45 (1H, s, H-1), 11.60 (1H, s, OH-3).
2
2
2
2
3-Hydroxy-4-morpholinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (17). Yield 91%, C18H21NO4,
mp 146-147°C (lit. 183-187°C [2], 190°C [16]). IR spectrum (KBr, cm-1): 3432, 2928, 1706, 1606, 1496, 1411, 1384, 1348,
1288, 1238, 1116, 1086, 866, 760. UV spectrum (dioxane, λmax, nm, log ε): 223 (4.33), 324 (4.26). PMR spectrum (400 MHz,
CDCl , δ, ppm, J/Hz): 1.82 (4H, m, CH -8, CH -9), 2.54 (2H, m, CH -10), 2.63 (4H, m, CH -2′, CH -6′), 2.74 (2H, m, CH -7),
3
2
2
2
2
2
2
3.77 (4H, m, CH -3′, CH -5′), 4.06 (2H, s, CH -4), 6.75 (1H, d, J = 8.8, H-2), 7.38 (1H, d, J = 8.8, H-1), 10.50 (1H, s, OH-3).
2
2
2
2-Chloro-3-hydroxy-4-morpholinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (18). Yield 89%,
C18H20ClNO4, mp 204-205°C. IR spectrum (KBr, cm-1): 3432, 2943, 1706, 1626, 1598, 1474, 1408, 1386, 1304, 1290, 1116,
1101, 1052, 868, 756. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.72), 228 (4.38), 329 (4.28). PMR spectrum (400 MHz,
CDCl , δ, ppm): 1.82 (4H, m, CH -8, CH -9), 2.54 (2H, m, CH -10), 2.70 (6H, m, CH -7, CH -2′, CH -6′), 3.79 (4H, m,
3
2
2
2
2
2
2
CH -3′, CH -5′), 4.09 (2H, s, CH -4), 7.48 (1H, s, H-1), 10.10 (1H, s, OH-3).
2
2
2
3-Hydroxy-4-[(4-methylpiperazino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (19). Yield 86%,
C19H24N2O3, mp 139-140°C (lit. 144-146°C [2]). IR spectrum (KBr, cm-1): 3402, 2941, 1712, 1627, 1602, 1500, 1383, 1298,
1283, 1241, 1095, 1068, 1008, 820. UV spectrum (EtOH, λmax, nm, log ε): 205 (4.97), 225 (4.49), 324 (4.48). PMR spectrum
(400 MHz, CDCl , δ, ppm, J/Hz): 1.82 (4H, m, CH -8, CH -9), 2.31 (3H, s, NCH ), 2.40-2.80 (4H, m, CH -2′, CH -3′, CH -5′,
3
2
2
3
2
2
2
CH -6′), 2.54 (2H, m, CH -10), 2.73 (2H, m, CH -7), 4.07 (2H, s, CH -4), 6.73 (1H, d, J = 8.8, H-2), 7.36 (1H, d, J = 8.8, H-1),
2
2
2
2
9.60 (1H, s, OH-3).
2-Chloro-3-hydroxy-4-[(4-methylpiperazino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (20). Yield
82%, C19H23ClN2O3, mp 186-187°C. IR spectrum (KBr, cm-1): 3413, 2937, 1721, 1597, 1479, 1458, 1384, 1346, 1300, 1101,
1048, 1005, 868, 818, 753. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.69), 229 (4.35), 333 (4.22). PMR spectrum
(400 MHz, CDCl , δ, ppm): 1.81 (4H, m, CH -8, CH -9), 2.32 (3H, s, NCH ), 2.40-2.80 (4H, m, CH -2′, CH -3′, CH -5′,
3
2
2
3
2
2
2
CH -6′), 2.52 (2H, m, CH -10), 2.71 (2H, m, CH -7), 4.09 (2H, s, CH -4), 7.46 (1H, s, H-1), 9.50 (1H, s, OH-3).
2
2
2
2
2-[(Dimethylamino)methyl]-3-hydroxy-4-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (21). Yield86%,
C17H21NO3, mp 162-163°C. IR spectrum (KBr, cm-1): 3425, 2934, 1704, 1616, 1593, 1476, 1394, 1312, 1256, 1185, 1125,
1025, 963, 760. UV spectrum (EtOH, λmax, nm, log ε): 209 (4.63), 227 (4.19), 328 (4.19). PMR spectrum (400 MHz, CDCl ,
3
δ, ppm): 1.78 (4H, m, CH -8, CH -9), 2.28 (3H, s, CH -4), 2.37 [6H, s, N(CH ) ], 2.54 (2H, m, CH -10), 2.70 (2H, m, CH -7),
2
2
3
3 2
2
2
3.85 (2H, s, CH -2), 7.00 (1H, s, H-1), 11.50 (1H, s, OH-3).
2
3-Hydroxy-4-methyl-2-(1-pyrrolydinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (22). Yield78%,
C19H23NO3, mp 149-150°C. IR spectrum (KBr, cm-1): 3448, 2936, 1702, 1612, 1460, 1420, 1396, 1312, 1187, 1171, 1124,
1071, 881, 790. UV spectrum (EtOH, λmax, nm, log ε): 209 (4.64), 227 (4.20), 329 (4.20). PMR spectrum (400 MHz, CDCl ,
3
δ, ppm): 1.82 (4H, m, CH -8, CH -9), 1.87 (4H, m, CH -3′, CH -4′), 2.28 (3H, s, CH -4), 2.54 (2H, m, CH -10), 2.65 (4H, m,
2
2
2
2
3
2
CH -2′, CH -5′), 2.72 (2H, m, CH -7), 3.87 (2H, s, CH -2), 7.02 (1H, s, H-1), 11.00 (1H, s, OH-3).
2
2
2
2
536

3-Hydroxy-4-methyl-2-piperidinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (23). Yield 76%,
C20H25NO3, mp 164-165°C. IR spectrum (KBr, cm-1): 3448, 2935, 1703, 1615, 1597, 1421, 1397, 1312, 1279, 1186, 1126,
1036, 787. UV spectrum (CH CN, λmax, nm, log ε): 209 (4.79), 227 (4.34), 329 (4.35). PMR spectrum (400 MHz, CDCl , δ,
3
3
ppm): 1.65 (6H, m, CH -3′, CH -4′, CH -5′), 1.81 (4H, m, CH -8, CH -9), 2.30 (3H, s, CH -4), 2.55 (2H, m, CH -10), 2.71
2
2
2
2
2
3
2
(2H, m, CH -7), 3.71 (2H, s, CH -2), 7.00 (1H, s, H-1), 9.80 (1H, s, OH-3).
2
2
3-Hydroxy-4-methyl-2-[(4-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one(24). Yield
76%, C21H27NO3, mp 136-137°C. IR spectrum (KBr, cm-1): 3433, 2932, 1700, 1612, 1597, 1458, 1393, 1373, 1312, 1262,
1160, 1127, 1072, 969, 759. UV spectrum (dioxane, λmax, nm, log ε): 212 (4.76), 228 (4.38), 324 (4.33). PMR spectrum
(400 MHz, CDCl , δ, ppm, J/Hz): 0.95 (3H, t, J = 6.4, CH -4′), 1.31 (2H, m, CH -3′α, CH -5′α), 1.45 (1H, m, H-4′), 1.68 (2H,
3
3
2
2
m, CH -3′β, CH -5′β), 1.81 (4H, m, CH -8, CH -9), 2.12 (2H, m, CH -2′α, CH -6′α), 2.29 (3H, s, CH -4), 2.55 (2H, m,
2
2
2
2
2
2
3
CH -10), 2.71 (2H, m, CH -7), 2.95 (2H, m, CH -2′β, CH -6′β), 3.73 (2H, s, CH -2), 7.00 (1H, s, H-1), 9.50 (1H, s, OH-3).
2
2
2
2
2
3-Hydroxy-4-methyl-2-[(4-methylpiperazino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (25). Yield
86%, C20H26N2O3, mp 162-163°C. IR spectrum (KBr, cm-1): 3433, 2934, 1694, 1610, 1596, 1458, 1393, 1313, 1269, 1185,
1169, 1130, 1085, 1009, 918, 816. UV spectrum (EtOH, λmax, nm, log ε): 209 (4.69), 227 (4.22), 328 (4.25). PMR spectrum
(400 MHz, CDCl , δ, ppm): 1.82 (4H, m, CH -8, CH -9), 2.29 (3H, s, CH -4), 2.32 (3H, s, NCH ), 2.40-2.80 (4H, m, CH -2′,
3
2
2
3
3
2
CH -3′, CH -5′, CH -6′), 2.54 (2H, m, CH -10), 2.71 (2H, m, CH -7), 3.76 (2H, s, CH -2), 7.03 (1H, s, H-1), 9.20 (1H, s,
2
2
2
2
2
2
OH-3).
2-[(Dimethylamino)methyl]-1-hydroxy-3-methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (26). Yield85%,
C17H21NO3, mp 160-161°C. IR spectrum (KBr, cm-1): 3434, 2944, 1706, 1609, 1579, 1429, 1318, 1248, 1220, 1160, 1101,
1021, 890, 773. UV spectrum (dioxane, λmax, nm, log ε): 215 (4.65), 233 (4.18), 262 (4.09), 299 (4.30). PMR spectrum
(400 MHz, CDCl , δ, ppm): 1.74 (4H, m, CH -8, CH -9), 2.26 (3H, s, CH -3), 2.35 [6H, s, N(CH ) ], 2.55 (2H, m, CH -10),
3
2
2
3
3 2
2
3.20 (2H, m, CH -7), 3.67 (2H, s, CH -2), 6.58 (1H, s, H-4), 11.00 (1H, s, OH-1).
2
2
1-Hydroxy-3-methyl-2-(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (27). Yield76%,
C19H23NO3, mp 145-146°C. IR spectrum (KBr, cm-1): 3434, 2934, 1690, 1622, 1601, 1459, 1411, 1379, 1338, 1150, 1116,
1073, 1046, 868. UV spectrum (dioxane, λmax, nm, log ε): 218 (4.55), 235 (4.14), 259 (4.03), 299 (4.23). PMR spectrum (400
MHz, CDCl , δ, ppm): 1.74 (4H, m, CH -8, CH -9), 1.88 (4H, m, CH -3′, CH -4′), 2.26 (3H, s, CH -3), 2.55 (2H, m, CH -10),
3
2
2
2
2
3
2
2.68 (4H, m, CH -2′, CH -5′), 3.21 (2H, m, CH -7), 3.85 (2H, s, CH -2), 6.57 (1H, s, H-4), 9.90 (1H, s, OH-1).
2
2
2
2
1-Hydroxy-3-methyl-2-piperidinomethyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (28). Yield 81%,
C20H25NO3, mp 141-142°C. IR spectrum (KBr, cm-1): 3424, 2946, 1697, 1621, 1602, 1463, 1415, 1383, 1198, 1150, 1114,
1041, 987, 860. UV spectrum (dioxane, λmax, nm, log ε): 218 (4.48), 237 (4.00), 258 (3.93), 301 (4.17). PMR spectrum
(400 MHz, CDCl , δ, ppm): 1.65 (6H, m, CH -3′, CH -4′, CH -5′), 1.75 (4H, m, CH -8, CH -9), 2.25 (3H, s, CH -3), 2.55 (2H,
3
2
2
2
2
2
3
m, CH -10), 2.90-3.10 (4H, m, CH -2′, CH -5′), 3.19 (2H, m, CH -7), 3.68 (2H, s, CH -2), 6.57 (1H, s, H-4), 9.50 (1H, s,
2
2
2
2
2
OH-1).
1-Hydroxy-3-methyl-2-[(4-methylpiperidino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (29). Yield
79%, C21H27NO3, mp 149-150°C. IR spectrum (KBr, cm-1): 3434, 2928, 1704, 1620, 1601, 1452, 1416, 1343, 1148, 1108,
1071, 972, 820. UV spectrum (dioxane, λmax, nm, log ε): 218 (4.52), 237 (4.08), 258 (3.97), 301 (4.17). 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), 1.44 (1H, m, H-4′), 1.68 (2H,
3
3
2
2
m, CH -3′β, CH -5′β), 1.75 (4H, m, CH -8, CH -9), 2.10 (2H, m, CH -2′α, CH -6′α), 2.25 (3H, s, CH -3), 2.55 (2H, m,
2
2
2
2
2
2
3
CH -10), 2.99 (2H, m, CH -2′β, CH -6′β), 3.21 (2H, m, CH -7), 3.69 (2H, t, CH -2), 6.57 (1H, s, H-4), 9.20 (1H, s, OH-1).
2
2
2
2
2
1-Hydroxy-3-methyl-2-[(4-methylpiperazino)methyl]-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (30). Yield
74%, C20H26N2O3, mp 179-180°C. IR spectrum (KBr, cm-1): 3449, 2930, 1700, 1619, 1604, 1460, 1415, 1351, 1415, 1352,
1286, 1151, 1111, 1093, 1011, 959, 821. UV spectrum (dioxane, λmax, nm, log ε): 218 (4.60), 237 (4.18), 258 (4.09), 298
(4.27). PMRspectrum (400 MHz, CDCl , δ, ppm): 1.74 (4H, m, CH -8, CH -9), 2.26 (3H, s, CH -3), 2.32 (3H, s, NCH ), 2.40-
3
2
2
3
3
2.80 (4H, m, CH -2′, CH -3′, CH -5′, CH -6′), 2.54 (2H, m, CH -10), 3.19 (2H, m, CH -7), 3.72 (2H, s, CH -2), 6.58 (1H, s,
2
2
2
2
2
2
2
H-4), 9.00 (1H, s, OH-1).
537

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3.
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