Synthesis of new 4-cyclohexylcoumarin derivatives

Article abstract of DOI:10.1055/s-2000-6395

4-Cyclohexyl-7-hydroxycoumarin (3) and 4-cyclohexyl-6-hydoxycoumarin (8) have been synthesized and used as key intermediates to prepare the potential antipsychotics 10 and 11 by coupling with a piperazine derivative.

Full text of DOI:10.1055/s-2000-6395

SHORT PAPER
643
Synthesis of New 4-Cyclohexylcoumarin Derivatives
Yagamare Fall,a Carmen Terán,a Marta Teijeira,b Lourdes Santana,*b Eugenio Uriarteb
aDepartamento de Química Física y Química Orgánica, Facultad de Ciencias, Universidad de Vigo, Spain
bDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15706 Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qolsant@usc.es
Received 11 October 1999
sants, sedatives and tranquilizers. Here we describe the
Abstract: 4-Cyclohexyl-7-hydroxycoumarin (3) and 4-cyclohexyl-
first synthesis of the 4-cyclohexylcoumarin derivatives 3
6-hydoxycoumarin (8) have been synthesized and used as key inter-
and 8 and their arylpiperazine derivatives 10 and 11,
mediates to prepare the potential antipsychotics 10 and 11 by cou-
which we hope may prove to have antipsychotic activity.
Structure-activity studies of a series of compounds includ-
ing 10 and 11 are currently in progress.
pling with a piperazine derivative.
Key words: 4-cyclohexylcoumarins, arylpiperazines, Wittig reac-
tion, Reformatsky reaction, cyclization, heterocycles
The synthesis of hydroxycoumarins 3 and 8 is shown in
Scheme 1. Keto diphenols 1 and 4, easily obtained by
Friedel-Crafts acylation,9 were subjected to a Wittig re-
action with ethoxycarbonylmethylenetriphenylphospho-
rane.10 Compound 1 gave a rather poor yield (24%) of the
expected 7-ethoxycoumarin 2, which was refluxed in a
mixture of acetic acid, acetic anhydride and hydroiodic
acid11 to afford 3 in 70% yield. Compound 4 was totally
unreactive under the same Wittig conditions, but Refor-
matsky reaction of its dimethylated derivative 59 gave an
80% yield of the tertiary alcohol 6. Dehydration of 6 with
thionyl chloride in pyridine afforded the a,b-unsaturated
ester 7 (83%), which on refluxing in a mixture of acetic
acid, acetic anhydride and hydroiodic acid gave 6-hy-
droxycoumarin 8 (68%).
Coumarins are a class of natural compounds that in recent
years have attracted growing synthetic interest1 while
some of them have been found to be useful in photo-
chemotherapy,2 antitumoral and anti-HIV therapy,3,4 or as
CNS-active compounds.5,6 In the course of our work on
the synthesis of potential antipsychotic compounds, we
have previously obtained a series of arylpiperazinecou-
marin derivatives with high affinity for dopamine and se-
rotonin receptors.7 To investigate how the substitution
pattern affects the pharmacological profile of this type of
molecule, we next wished to prepare a series of coumarins
with a bulky lipophilic group such as cyclohexyl at posi-
tion 4. The only previous reference to 4-cyclohexylcou-
marin derivatives in the literature appears to be a 1975 US
patent8 describing a useful intermediate in the synthesis of
chromans and chromenes used as nervous system depres-
The sodium salts of coumarins 3 and 8 were coupled with
1-(3-chloropropyl)-4-(p-methoxyphenyl)piperazine (9) in
dimethylformamide12 to afford compounds 10 and 11, re-
Reaction conditions: (i) Ph3PCHCO2Et, 180°C (24%); (ii) HI/Ac2O/AcOH (70%); (iii) BrCH2CO2Et/Zn/benzene (80%); (iv) SOCl2/pyr (83%);
(v) HI/Ac2O/HOAc (68%)
Scheme 1
Synthesis 2000, No. 5, 643–645 ISSN 0039-7881 © Thieme Stuttgart · New York

644
Y. Fall et al.
SHORT PAPER
1. 3, 8 / DMF / NaH, 100 ºC, 1h
2. 9 / NaI, 100 ºC, overnight
+
Cl
O
HO
CH3O
N
N
CH3O
N
N
O
O
O
O
9
10, 11
79-80%
3, 8
Scheme 2
spectively, in approximately 80% yield (Scheme 2). Com-
pound 9 was readily synthesized from N-(p-methoxy-
phenyl)piperazine and 1-bromo-3-chloropropane.13
IR (KBr): n = 3490, 2852, 1720, 1675 cm-1.
1H NMR (CDCl3): d = 7.16 (d, 1 H, J = 2.90 Hz), 6.76 (d, 1 H,
J = 8.78 Hz), 6.70 (dd, 1 H, J = 8.78, 2.90 Hz), 4.25 (s, 1 H), 3.82-
3.91 (m, 2 H, CO2CH2CH3), 3.76 (s, 3 H, CH3O), 3.41 (d, 1 H,
J = 14.70 Hz, CHHCO2Et), 2.78 (d, 1 H, J = 14.70, CHHCO2Et),
0.83-2.00 (m, 10 H), 0.95 (t, 3 H, J = 7.05 Hz, CO2CH2CH3).
Melting points were determined in a Reichert Kofler thermopan or
in capillary tubes in a Büchi 510 apparatus, and are uncorrected. IR
1
MS: m/z = 336 (M+), 253, 165.
spectra were recorded in a Perkin-Elmer 1640FT spectrometer. H
and 13C NMR spectra were recorded in a Bruker AMX spectrometer
at 300 and 75.47 MHz, respectively, using TMS as internal standard
(chemical shifts in d values, J in Hz). Mass spectra were obtained
using a Hewlett Packard 5988A spectrometer. Elemental analyses
were performed by a Perkin-Elmer 240B microanalyser (C ± 0.29,
H ± 0.28). Silica gel (Merck 60, 230-400 mesh) was used for flash
chromatography (FC). Analytical TLC was performed on plates
precoated with silica gel (Merck 60 F254, 0.25 mm).
Ethyl 3-Cyclohexyl-3-hydroxy-3-(2,5-dimethoxyphenyl)-2-pro-
penoate (7)
SOCl2 (142 mL, 1.95 mmol) was added to a solution of 6 (420 mg,
1.95 mmol) in pyridine (800 mL) at 0ºC. The mixture was stirred at
0ºC for 30 min and then at r.t. for 3 h. The mixture was poured into
ice-water and extracted with CH2Cl2 (3 x 10 mL). The combined or-
ganic phases were washed with satd aq CuSO4 solution, dried
(Na2SO4), and the solvent was evaporated to afford 7, which was
used in the next step without further purification. Yield: 330 mg
(83%).
4-Cyclohexyl-7-ethoxycoumarin (2)
A mixture of 110 (1g, 4.54 mmol) and ethoxycarbonylmethylene-
triphenylphosphorane (5.7 g, 16.36 mmol) was heated at 180ºC for
48 h. The solid residue was chromatographed on silica gel with 95:5
hexane/EtOAc as eluent to afford the coumarin 2. Yield 300 mg
(24%); mp 89-91°C.
IR (KBr): n = 2935, 1708, 1615, 1438 cm-1.
1H NMR (CDCl3): d = 8.61 (d, 1 H, J = 8.78 Hz), 6.77 (dd, 1 H,
J = 8.78, 2.62 Hz), 6.51 (d, 1 H, J = 2.62 Hz), 5.87 (d, 1 H, J = 1.05
Hz), 3.95 (q, 2 H, J = 7.12 Hz, CO2CH2CH3), 3.75 (s, 3 H, CH3O),
3.72 (s, 3 H, CH3O), 2.24 (m, 1 H), 1.60-1.80 (m, 6 H), 1.10-1.35
(m, 4 H), 1.04 (t, 3 H, J = 7.12 Hz, CO2CH2CH3).
IR (KBr): n = 3728, 2850, 1732, 1582 cm-1.
1H NMR (CDCl3): d = 7.55 (d, 1 H, H-5, J = 8.88 Hz), 6.85 (dd, 1
H, H-6, J = 8.88, 2.40 Hz), 6.80 (d, 1 H, H-8, J = 2.40 Hz), 6.15 (s,
1 H, H-3), 4.10 (q, 2 H, J = 7.13 Hz), 2.86 (t, 1 H, J = 11.25 Hz),
2.00-1.80 (m, 6 H), 1.55-1.20 (m, 7 H).
MS: m/z = 318 (M+), 245, 174.
4-Cyclohexyl-6-hydroxycoumarin (8)
MS: m/z = 272 (M+), 217, 204, 176.
HI (10 mL) was added to a solution of 7 (330 mg, 1.03 mmol) in
AcOH (5 mL) and Ac2O (5 mL). The mixture was refluxed for 2 h,
allowed to reach r.t. and H2O (10 mL) was added. After stirring for
30 min, the precipitated hydroxycoumarin 8 was filtered out. Yield:
170 mg (68%); mp 198-200°C.
IR (KBr): n = 2935, 1708, 1615, 1438 cm-1.
1H NMR (CDCl3): d = 8.61 (d, 1 H, H-8, J = 8.87 Hz), 7.10 (d, 1 H,
H-5, J = 2.80 Hz), 7.02 (dd, 1 H, H-7, J = 8.80, 2.80 Hz), 6.29 (s, 1
H, H-4), 2.80 (t, 1 H, J = 11.25 Hz), 2.10-1.25 (m, 10 H).
4-Cyclohexyl-7-hydroxycoumarin (3)
HI (2 mL) was added to a solution of 7-ethoxycoumarin 2 (110 mg,
0.40 mmol) in a mixture of AcOH (1 mL) and Ac2O (1 mL). The
mixture was refluxed for 2 h, allowed to reach r.t. and H2O (3 mL)
was added. After stirring for 30 min, the precipitated 7-hydroxycou-
marin 3 was filtered out. Yield 70 mg (70%); mp 176-178°C.
IR (KBr): n = 3711, 2848, 1686, 1508 cm-1.
1H NMR (CDCl3): d = 7.55 (d, 1 H, H-5, J = 8.88 Hz), 7.08 (d, 1 H,
H-8, J = 2.44 Hz), 6.87 (dd, 1 H, H-6, J = 8.88, 2.44 Hz), 6.16 (s, 1
H, H-3), 2.86 (t, 1 H, J = 11.25 Hz), 1.96-1.80 (m, 6 H), 1.49-1.27
(m, 4 H).
13C NMR (CDCl3): d = 162.18, 160.78, 152.28, 148.50, 119.55,
118.49, 112.02, 109.21, 39.03, 32.34, 26.46, 25.97.
MS: m/z = 244 (M+), 215, 201, 187, 173.
MS: m/z = 244 (M+), 215, 201, 189, 176, 161, 148.
Arylpiperazinopropyloxycoumarins 10 and 11; General Proce-
dure
Ethyl 3-Cyclohexyl-3-hydroxy-3-(2,5-dimethoxyphenyl)pro-
panoate (6)
NaH (17 mg, 0.430 mmol) was added to a solution of hydroxycou-
marin 3 or 8 (70 mg, 0.286 mmol) in DMF (4 mL) and the mixture
was stirred at 100°C for 1 h. After addition of a solution of 1-(3-
chloropropyl)-4-(p-methoxyphenyl)piperazine (9; 115 mg, 0.430
mmol) in DMF (1 mL), followed by NaI (64 mg, 0.430 mmol), the
mixture was stirred overnight at 100°C. The DMF was evaporated
and the residue chromatographed on silica gel using 1:3 hexane/
EtOAc as eluent to afford compound 10 or 11.
A solution of ketone 5 (560 mg, 2.62 mmol) and ethyl bromoacetate
(2.5 mL, 22.6 mmol) in benzene (5 mL) was added dropwise to a
refluxing mixture of zinc (1.47 g, 22.5 mmol) in benzene (5 mL).
When addition was complete the mixture was refluxed for further 3
h and allowed to cool to r.t. The mixture was poured into ice-water,
extracted with EtOAc (3 x 10 mL), and the organic phase was dried
(Na2SO4). Filtration and solvent evaporation afforded a residue that
was chromatographed on silica gel using 90:10 hexane/EtOAc as
eluent to give 6 as an oil. Yield: 607 mg (80%).
Synthesis 2000, No. 5, 643–645 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of New 4-Cyclohexylcoumarin Derivatives
645
4-Cyclohexyl-7-{3-[4-(p-methoxyphenyl)-1-piperazinyl]propyl-
oxy}coumarin (10)
Yield: 109 mg (80%); mp (10•2HCl) 146-147°C.
IR (KBr): n = 3432, 2930, 2367, 1720, 1608 cm-1.
1H NMR (CDCl3): d = 7.53 (d, 1 H, H-5, J = 8.74 Hz), 6.80-6.91
(m, 6 H), 6.11 (s, 1 H, H-3), 4.08 (t, 2 H, CH2O, J = 6.23 Hz), 3.74
(s, 3 H, CH3O), 3.09 [m, 4 H, N(CH2)2], 2.82 (m, 1 H), 2.61 [m, 6
H, (CH2)2NCH2], 2.01 (m, 2 H), 1.29-1.48 (m, 5 H), 1.79-1.95 (m,
5 H).
13C NMR (CDCl3): d = 162.44, 162.13, 161.48, 156.00, 154.18,
146.05, 125.33, 118.57, 114.79, 112.98, 112.63, 108.79, 102.13,
67.15, 55.93, 55.32, 53.77, 50.99, 39.42, 32.84, 30.10, 26.93, 26.46.
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Article Identifier:
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Synthesis 2000, No. 5, 643–645 ISSN 0039-7881 © Thieme Stuttgart · New York