Synthesis of 2(3H)-benzoxazolone derivatives as potential melatonin receptor ligands

Article abstract of DOI:10.3987/com-03-9859

This article reports the synthesis of new 2(3H)-benzoxazolone-based ligands for the melatonin receptors in which an acetamidopropyl side-chain was incorporated. Construction of the acetamidopropyl moiety was achieved via a Wadsworth-Emmons approach. Altho

Full text of DOI:10.3987/com-03-9859

HETEROCYCLES, Vol. 60, No. 12, 2003, pp. 2621 - 2630
Received, 14th July, 2003, Accepted, 26th September, 2003, Published online, 30th September, 2003
SYNTHESIS OF 2(3H)-BENZOXAZOLONE DERIVATIVES AS
POTENTIAL MELATONIN RECEPTOR LIGANDS
Christophe Mésangeau1, Jacques H. Poupaert2, Pascal Carato1*, and Saïd Yous1
1Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et
Biologiques de Lille, 3, rue du Professeur Laguesse, BP 83, F-59006 Lille, France.
Fax: 03 20 96 43 75; e-mail: pcarato@phare.univ-lille2.fr
2Unité de Chimie Pharmaceutique, Ecole de Pharmacie, Faculté de Médecine,
Université Catholique de Louvain, Avenue E. Mounier 73 (UCL 7343), B-1200
Bruxelles, Belgium
Abstract – This article reports the synthesis of new 2(3H)-benzoxazolone-based
ligands for the melatonin receptors in which an acetamidopropyl side-chain was
incorporated. Construction of the acetamidopropyl moiety was achieved via a
Wadsworth-Emmons approach. Although these compounds can be seen as
derivatives of N-[3-(3-methoxyphenyl)propyl]acetamide (MPPA), which is the
exact analogue of melatonin in which the 1,2-indole nitrogen atoms are deleted,
they exhibit lower affinities for the melatonin receptors probably due to an
unfavourable steric bulk and hydrophilic interactions.
Melatonin (N-acetyl-5-methoxytryptamine, MT), a neurohormone principally synthesized and secreted by
the pineal gland during the dark period in animal and humans1,2 plays a central role in the regulation of
circadian rhythm and, as a chronobiotic, can provide valuable therapy in the management of jet lag3 and
sleep disorders4 particularly those occasioned by shift work. Melatonin exerts its effects through at least
three targets : two G-protein-coupled receptors, MT1 and MT2,5,6 and a binding site, MT3/QR2.7 In the
course of our search for new melatonin receptor ligands, we previously reported8-10 various series of
analogues involving the use of naphthalene, benzofuran, benzothiophene, and tetralin as central template.
Most of them exhibited high affinity on both MT1 and MT2 receptors. As a part of this ongoing research
program, the 2(3H)-benzoxazolone heterocycle11 was also investigated as pivotal structure for the β-
acetamidoethyl side-chain but the resulting analogues (6-AEB, Figure 1) showed only moderate affinities
for the melatonin receptors.

In recent years, Garrat et al.12 described compounds with a phenyl moiety bearing the acetamidoethyl
(MPEA) and the acetamidopropyl side-chain (MPPA) as structurally simplified ligands of melatonin
receptors and showed that MPPA possessed better affinities than its lower homologue. In accordance with
previous publication of our group and Garrat’s report, we decided to replace the ethylene moiety of 6-
AEB by a propylene side-chain (6-APB). As part of this search, we also decided to synthesise the 5-
isomer of this compound (5-APB) and to limit the conformational freedom of the acetamidopropyl side-
chain of compound (12) by preparing compound (17) in which this chain is embedded into a cyclic
structure (Figure 1).
NHCOCH3
NHCOCH3
NHCOCH3
CH3
O
CH3
O
O
O
N
R
N
H
6-AEB
MT
MPPA
NHCOCH3
NHCOCH3
NHCOCH3
R
CH3
O
N
N
O
O
O
N
O
O
CH3
10 R=H
12 R=CH3
5
17
6-APB
5-APB
Figure 1
RESULTS AND DISCUSSION
Compound (5) was prepared as outlined in Scheme 1. The bromoacetyl derivative (2) was obtained by a
Friedel-Crafts acid-catalyzed acylation of 1 using bromoacetic acid and polyphosphoric acid (70 % yield).
Subsequent reduction of the ketone carbonyl group was performed using triethylsilane in trifluoroacetic
acid (83 % yield) as previously described.13,14 Substitution of the bromoethyl derivative (3) with
potassium cyanide in DMSO led to 4 (83 % yield) which was then hydrogenated in the presence of Raney
nickel as catalyst in acetic anhydride to give the N-acetyl derivative (5) (71 % yield).

Br
O
Br
O
O
O
(C2H5)3SiH
CF3CO2H
BrCH2CO2H
PPA
O
O
O
N
N
N
CH3
3
CH3
CH3
2
1
KCN
DMSO
CN
NHCOCH3
O
O
H2/Raney Ni
(CH3CO)2O
O
O
N
N
CH3
CH3
4
5
Scheme 1
The key intermediate in the synthesis of compounds (10) and (12) is the nitrile (8) which was prepared as
shown in Scheme 2.
CH3
CN
O
CN
O
O
O
N+
CHO
N+
HN
O
(C2H5O)2P(O)CH2CN
NaH, THF
O
1) HCOONH4, 10% Pd/C
2) CH3OCOCl, (C2H5)3N
HO
HO
HO
6
7
K2CO3
DMF
NHCOCH3
HCl 1M
NHCOCH3
CN
CH3
O
H
H
N
N
N
H2/Raney Ni
O
O
O
(CH3CO)2O
O
O
O
10
9
8
CH3I
DMF
K2CO3
NHCOCH3
CN
CH3
CH3
N
N
H2/Raney Ni
O
O
(CH3CO)2O
O
O
12
11
Scheme 2

Treatment of 4-hydroxy-3-nitrobenzaldehyde with diethyl cyanomethylphosphonate and NaH in
tetrahydrofuran according to the Wadsworth-Emmons15 reaction gave the nitrile (6) (70 % yield). The
stereochemistry of this compound was assigned on the basis of the coupling constant values of the
ethylenic protons (J = 16.4 Hz), which were consistent with the values expected for the (E)-stereoisomer.
Selective reduction of the nitro group of 6 was accomplished with ammonium formate and palladium on
charcoal in methanol and the amino group was immediately converted into methyl carbamate (7) (70 %
yield) by treatment in ethyl acetate with methyl chloroformate and triethylamine. Compound (7) was
finally heated in DMF in the presence of potassium carbonate to afford the benzoxazolinonic compound
(8) (70 % yield). The N-acetyl derivative (10) was obtained by hydrogenation of 8 in the presence of
Raney nickel in acetic anhydride (76 % yield) and selective desacetylation of 9 by treatment in 1M HCl
(82 % yield). On the other hand, N-methylation of 8 with methyl iodide and potassium carbonate in DMF
gave 11 (71 % yield) which upon reduction of the nitrile group in acetic anhydride provided 12 (37 %
yield).
Compound (17) was prepared in five steps starting from 3-methyl-2(3H)-benzoxazolone (Scheme 3).
CH3
N
CH3
N
succinic anhydride
AlCl3
O
O
COOH
O
O
1
13
O
(C2H5)3SiH
CF3CO2H
O
CH3
N
CH3
N
PPA
O
O
COOH
O
O
14
15
THF
NaH
(C2H5O)2P(O)CH2CN
NHCOCH3
CN
CH3
CH3
N
N
H2/Raney Ni
(CH3CO)2O
O
O
O
O
16
17
Scheme 3

16
Tetralone (15) was obtained according to previously described procedure. The acid (13) was obtained
via a Friedel-Crafts acylation of the starting material with succinic anhydride using the AlCl3-DMF
reagent. Reduction of the ketone carbonyl group of 13 gave 14. This compound was then cyclised to the
tetralone (15) (69 % yield) by heating in polyphosphoric acid. The acetonitrile (16) was prepared from 15
1
via a Wadsworth-Emmons reaction (46 % yield). Assignment of its configuration was not easy by H-
NMR spectrum due to the absence of neighboring protons on the vicinal carbon and was therefore
tentatively ascribed on the basis of molecular mechanisms (MM2) and semi-quantum mechanisms
calculations (PM3 and PM3 COSMO). Indeed, by the MM2 method, a difference of steric energy of 3.0
Kcal/mol in favor of the E-isomer while the PM3 and PM3 COSMO methods gave a difference of heat of
formation of 2.2 and 3.3 Kcal/mol, respectively, always in favor of the E-isomer. In all cases thus, the E-
configuration was favored. Compound (16) was finally hydrogenated in acetic anhydride as described
above to give 17 (47 % yield).
In conclusion, this article reports the synthesis of new 2(3H)-benzoxazolone-based ligands for the
melatonin receptors in which an acetamidopropyl side-chain was incorporated. Construction of the
acetamidopropyl moiety was expeditiously achieved by Wadsworth-Emmons approach. While there is a
considerable body of literature pertinent to the structure activity - relationships of MT1 receptor ligands,
including detailed ComFa studies,17 the MT2 receptor has been by far less intensively investigated.
Among the newly synthesized melatonin analogs, the only compounds that showed noticeable affinities
for melatonin receptors were compounds (12) and (17) (IC50: 6.7.10-6M and 1.43.10-7M, respectively),
and this only at MT2 receptor sites. All other compounds exhibited disappointingly IC50's>10-5 M, both at
MT1 and MT2 receptor sites. Although the compounds we report here can be effectively considered as
close modifications of N-[3-(3-methoxyphenyl)propyl]acetamide (MPPA), which is as a matter of fact the
exact analogue of melatonin in which the 1,2-indole nitrogen atoms have been deleted, they demonstrated
much lower affinities for the melatonin receptors most likely due to unfavourable steric bulk and
hydrophilic interactions. Among all the original ligands obtained, compound (17) in view of the
selectivity for MT2 it exhibited (IC50 MT1/MT2 = 8.2) has been selected as a valuable lead compound for
further elaborations of selective MT2 receptor ligands.
EXPERIMENTAL
Melting points were determined on a Büchi SMP-535 apparatus and are uncorrected. IR spectra were
recorded on a Brüker Vector 22 spectrophotometer using KBr pellets. 1H NMR spectra were recorded on
a Brüker AC 300 instrument in DMSO-d6 using TMS as an internal reference. Elemental analysis were

performed by the analytical center of C.N.R.S. of Vernaison (France) and are within -/+ 0.4 of the
theoretical values.
3-(3-Methyl-2(3H)-benzoxazol-6-yl)propionitrile (4)
To a suspension of potassium cyanide (5.6 g, 86 mmol) in DMF (250 mL) was slowly added compound
(3) (12.5 g, 49 mmol). The mixture was stirred at 60°C for 24 h and poured into water. The precipitate
was filtered, washed with water and dried. Recrystallization from toluene-cyclohexane (9-1) afforded 4
(8.96 g, 83 %) as white solid. mp 145-147°C. IR ν 2241, 1763 cm-1. 1H NMR δ 2.82 (t, J = 6.3 Hz, 2H) ;
2.92 (t, J = 6.3 Hz, 2H) ; 3.25 (s, 3H) ; 7.15 (d, J = 7.7 Hz, 1H) ; 7.20 (d, J = 7.7 Hz, 1H) ; 7.32 (s, 1H).
Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.50; H, 5.06; N, 13.64.
N-[3-(3-Methyl-2(3H)-benzoxazol-6-yl)propyl]acetamide (5)
A solution of 4 (1.2 g, 6 mmol) in acetic anhydride (150 mL) was hydrogenated over Raney nickel (0.2 g)
under pressure (60 bar) at 60°C for 6 h. After filtration and evaporation, the residue was dissolved in
methylene chloride, washed with 0.1 M NaOH, dried (MgSO4) and evaporated under reduced pressure.
Recrystallization from ethyl acetate afforded 5 (1.06 g, 71 %) as white solid. mp 128-130°C. IR ν 3304,
1766, 1635 cm-1. 1H NMR δ 1.68 (qu, J = 6.8 Hz, 2H) ; 1.80 (s, 3H) ; 2.60 (t, J = 6.8 Hz, 2H) ; 3.02 (m,
2H) ; 3.30 (s, 3H) ; 7.06 (d, J = 8.0 Hz, 1H) ; 7.15 (d, J = 8.0 Hz, 1H) ; 7.21 (s, 1H) ; 7.86 (br s, 1H). Anal.
Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.75; H, 6.58; N, 11.35.
(E)-3-(4-Hydroxy-3-nitrophenyl)acrylonitrile (6)
Under stirring and N2, a solution of diethyl cyanomethylphosphonate (23.3 mL, 144 mmol) in anhydrous
THF (40 mL) was added dropwise to a mixture of 60 % NaH (5.7 g, 144 mmol) in anhydrous THF (100
mL) cooled at 0°C. After 1 h, a solution of 4-hydroxy-3-nitrobenzaldehyde (8 g, 48 mmol) in anhydrous
THF (40 mL) was added dropwise and the mixture was stirred at rt for 1 h. The mixture was then poured
into water and 1M HCl was added until pH 2.0. The precipitate was collected by filtration, washed with
water and dried. Recrystallization from toluene afforded 6 (6.39 g, 70 %) as yellow solid. mp 178°C. IR
ν 3260, 2216 cm-1. 1H NMR δ 6.43 (d, J = 16.4 Hz, 1H) ; 7.18 (d, J = 8.6 Hz, 1H) ; 7.64 (d, J = 16.4 Hz,
1H) ; 7.85 (dd, J = 8.6, 2.2 Hz, 1H) ; 8.21 (d, J = 2.2 Hz, 1H) ; 11.70 (s, 1H). Anal. Calcd for C9H6N2O3:
C, 56.85; H, 3.18; N, 14.73. Found: C, 57.02; H, 3.25; N, 14.62.
(E)-N-[5-(2-Cyanovinyl)-2-hydroxyphenyl]methyl carbamate (7)
To a stirred suspension of 6 (4.5 g, 23.7 mmol) and palladium on charcoal (1.2 g) in methanol (80 mL) at
40°C was added anhydrous ammonium formate (9 g, 142 mmol). The resulting mixture was stirred at

40°C for 1 h and the catalyst was removed by filtration through a celite pad. The filtrate was evaporated
under reduced pressure, then the residue was taken up in water and extracted with ethyl acetate.
Triethylamine (4.9 mL, 35 mmol) and methyl chloroformate (2.2 mL, 28.5 mmol) were added to the
solution at 0°C. The mixture was stirred for 1 h, washed with 0.5 M HCl and with water. The organic
phase was dried (MgSO4) and evaporated under reduced pressure. Recrystallization from toluene afforded
1
7 (3.62 g, 70 %) as white solid. mp 183-186°C. IR ν 3367, 3187, 2213, 1694 cm-1. H NMR δ 3.65 (s,
3H) ; 6.13 (d, J = 16.7 Hz, 1H) ; 6.88 (d, J = 8.5 Hz, 1H) ; 7.27 (dd, J = 8.5, 1.5 Hz, 1H) ; 7.51 (d, J = 16.7
Hz, 1H) ; 7.78 (s, 1H) ; 8.50 (br s, 1H) ; 10.46 (br s, 1H). Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62;
N, 12.84. Found: C, 60.41; H, 4.52; N, 12.99.
(E)-3-[2(3H)-benzoxazol-5-yl]acrylonitrile (8)
To a solution of 7 (2 g, 9.2 mmol) in DMF (60 mL) was added potassium carbonate (2.5 g, 18 mmol).
The reaction mixture was heated under reflux for 20 min, poured into water and the precipitate was
collected by filtration. Recrystallization from toluene-acetonitrile (1-1) afforded 8 (1.20 g, 70 %) as white
solid. mp 261-264°C. IR ν 3348, 2210, 1776 cm-1. 1H NMR δ 6.45 (d, J = 16.0 Hz, 1H) ; 7.37 (m, 3H) ;
7.67 (d, J = 16.0 Hz, 1H) ; 11.90 (br s, 1H). Anal. Calcd for C10H6N2O2: C, 64.52; H, 3.25; N, 15.05.
Found: C, 64.21; H, 3.35; N, 15.01.
N-[3-(3-Acetyl-2(3H)-benzoxazol-5-yl)propyl]acetamide (9)
A solution of 8 (1.2 g, 6.5 mmol) in acetic anhydride (120 mL) was hydrogenated over Raney nickel (0.3
g) under pressure (50 bar) at 50°C for 30 h. After filtration and evaporation, the residue was dissolved in
ethyl acetate, washed with an aqueous solution of potassium carbonate and with water. The solvent was
dried (MgSO4) and evaporated to dryness. Recrystallization from toluene afforded 9 (1.36 g, 76 %) as
1
white solid. mp 149-153°C. IR ν 3319, 1797, 1719, 1642 cm-1. H NMR δ 1.67 (m, 2H) ; 1.80 (s, 3H) ;
2.60 (s, 3H) ; 2.64 (t, J = 7.4 Hz, 2H) ; 3.03 (m, 2H) ; 7.14 (d, J = 8.3 Hz, 1H) ; 7.32 (d, J = 8.3 Hz, 1H) ;
7.81 (s, 1H) ; 7.88 (br s, 1H). Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.71;
H, 5.92; N, 10.05.
N-[3-(2(3H)-Benzoxazol-5-yl)propyl]acetamide (10)
A suspension of 9 (1.1 g, 4 mmol) in 1M HCl (40 mL) was heated at 50°C for 15 h and concentrated in
vacuo. The resulting precipitate was collected by filtration and dried. Recrystallization from water-
ethanol (1-1) afforded 10 (0.77 g, 82 %) as white solid. mp 164-166°C. IR ν 3345, 1761, 1625 cm-1. 1H
NMR δ 1.63 (m, 2H) ; 1.80 (s, 3H) ; 2.57 (t, J = 7.5 Hz, 2H) ; 3.02 (m, 2H) ; 6.90 (m, 2H) ; 7.16 (d, J=

8.3 Hz, 1H) ; 7.86 (br s, 1H) ; 11.56 (br s, 1H). Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.38; H, 6.01; N, 11.87.
(E)-3-(3-Methyl-2(3H)-benzoxazol-5-yl)acrylonitrile (11)
Potassium carbonate (3.1 g, 22.5 mmol) was added to a solution of 8 (1.4 g, 7.5 mmol) in DMF (30 mL).
The reaction mixture was refluxed for 30 min and methyl iodide (0.7 mL, 11 mmol) was slowly added.
After stirring at reflux for 30 min, the solution was poured into water and the precipitate was collected by
filtration. Recrystallization from toluene afforded 11 (1.07 g, 71 %) as white solid. mp 220-222°C. IR ν
2214, 1771 cm-1. 1H NMR δ 3.34 (s, 3H) ; 6.47 (d, J = 16.8 Hz, 1H) ; 7.40 (m, 3H) ; 7.68 (d, J = 16.8 Hz,
1H). Anal. Calcd for C11H8N2O2: C, 66.00; H, 4.03; N, 13.99. Found: C, 65.82; H, 4.15; N, 14.24.
N-[3-(3-Methyl-2(3H)-benzoxazol-5-yl)propyl]acetamide (12)
Starting from 11 (1 g, 5 mmol) the reaction was carried out as described for 9. Recrystallization from
1
ethyl acetate afforded 12 (0.46 g, 37 %) as white solid. mp 137-138°C. IR ν 3308, 1757, 1627 cm-1. H
NMR δ 1.70 (m, 2H) ; 1.81 (s, 3H) ; 2.62 (t, J = 7.6 Hz, 2H) ; 3.04 (m, 2H) ; 3.32 (s, 3H) ; 6.96 (d, J= 8.2
Hz, 1H) ; 7.12 (s, 1H) ; 7.22 (d, J = 8.2 Hz, 1H) ; 7.88 (br s, 1H). Anal. Calcd for C13H16N2O3: C, 62.89;
H, 6.50; N, 11.28. Found: C, 62.63; H, 6.59; N, 11.12.
3-Methyl-2,5-dioxo-cyclohexa(f)benzoxazole (15)
Under mechanical stirring, a mixture of polyphosphoric acid (50 g) and 14 (5 g, 21 mmol) was heated at
70°C for 2 h. After cooling, the reaction mixture was poured into ice. The precipitate was collected by
filtration and dried. Recrystallization from acetonitrile afforded 15 (3.15 g, 69 %) as white solid. mp 172-
174°C. IR ν 1755, 1625 cm-1. 1H NMR δ 2.03 (m, 2H) ; 2.61 (t, J = 6.1 Hz, 2H) ; 2.97 (t, J = 6.1 Hz, 2H) ;
3.36 (s, 3H) ; 7.33 (s, 1H) ; 7.65 (s, 1H). Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.16; H, 5.16; N, 6.34.
(E)-(3-Methyl-2-oxocyclohexa(f)benzoxazol-5-ylidene)acetonitrile (16)
Under stirring and N2, a solution of diethyl cyanomethylphosphonate (3.1 mL, 19 mmol) in anhydrous
THF (20 mL) was added dropwise to a mixture of 60 % NaH (0.8 g, 19 mmol) in anhydrous THF (30
mL) cooled at 0°C. After 1 h, a solution of 15 (2.8 g, 13 mmol) in anhydrous THF (40 mL) was added
dropwise and the mixture was stirred at rt for 1 h. The mixture was then poured into water and extracted
with ether. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness.
Recrystallization from toluene-acetonitrile (4-1) afforded 16 (1.44 g, 46 %) as white solid. mp 258-
262°C. IR ν 2204, 1775 cm-1. 1H NMR δ 1.83 (m, 2H) ; 2.80 (t, J = 5.9 Hz, 2H) ; 2.86 (t, J = 5.9 Hz, 2H) ;

3.33 (s, 3H) ; 6.28 (s, 1H) ; 7.20 (s, 1H) ; 7.70 (s, 1H). Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N,
11.66. Found: C, 70.12; H, 5.15; N, 11.39.
N-[2-(3-Methyl-2-oxocyclohexa(f)benzoxazol-5-yl)ethyl]acetamide (17)
Starting from 16 (1.4 g, 4.2 mmol) the reaction was carried out as described for 9. Recrystallization from
toluene afforded 17 (0.57 g, 47 %) as white solid. mp 121-123°C. IR ν 3299, 1775, 1634 cm-1. 1H NMR
δ 1.70 (m, 9H) ; 2.80 (m, 3H) ; 3.14 (t, J = 5.6 Hz, 2H) ; 3.31 (s, 3H) ; 7.00 (s, 1H) ; 7.01 (s, 1H) ; 7.88
(br s, 1H). Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.54; H, 7.14; N, 9.88.
ACKNOWLEDGEMENT
The authors are grateful to Dr. C. Bochu (Laboratoire d’Application de Résonance Magnétique Nucléaire
de l’Université de Lille 2) for his help in the interpretation of the 1H-NMR spectra.
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