3740
Helvetica Chimica Acta Vol. 84 (2001)
HPLC: reversed-phase C18 column, Shimadzu LC-10AS pump, variable-wavelength Shimadzu SPD-10A UV/
VIS detector set at 260 nm; Spectra-Physics Chromjet integrator. UV Spectra: Perkin-Elmer Lambda 2
spectrometer; la
in nm. Fluorescence spectra: Fluorolog 2 spectrofluorimeter; lf
in nm. IR Spectra:
max
max
Perkin-Elmer Spectrum-RXI FT-IR spectrometer; KBr pellets or thin films on NaCl; n in cmÀ1 1H-NMR
.
Spectra: Bruker AC-200 P spectrometer operating at 200 MHz; chemical shifts (d) in ppm (referenced internally
to solvent signals), and coupling constant J in Hz. Elemental analyses were performed by CNRS Laboratory
(Vernaison, France).
Syntheses. Ethyl 7-(Diethylamino)-2-oxo-2H-[1]benzopyran-3-carboxylate (3). Compound 3 was prepared
according to the procedure described for the synthesis of Coumarin 343 methyl ester [14]. Diethyl malonate
(16.5 ml, 150 mmol) and 4-(diethylamino)-2-hydroxybenzaldehyde (20 g, 100 mmol) were dissolved in
piperidine (30 ml) and MeCN (300 ml). The soln. was heated at reflux for 3 h and then slowly distilled. The
remaining crude product was purified by chromatography: AcOEt/CH2Cl2 1:2 (v/v): 26 g (90%) of 3. M.p.: 90
928 ([16]: 80 828). IR: 1735 (CO, ester). 1H-NMR (CDCl3): 8.43 (s, HÀC(4)); 7.37 (d, J 9, HÀC(5)); 6.60
(dd, J 2.5, 9, HÀC(6)); 6.47 (d, J 2.5, HÀC(8)); 4.39 (q, MeCH2O); 3.45 (q, (MeCH2)2N); 1.39 (t,
MeCH2O); 1.23 (t, (MeCH2)2N)). Anal. calc. for C16H19NO4: C 66.42, H 6.63, N 4.84; found: C 66.53, H 6.64, N
5.18.
7-(Diethylamino)-2-oxo-2H-[1]benzopyran-3-carboxylic Acid (4). A soln. of 3 (17 g, 59 mmol) and KOH
(5.3 g, 94.4 mmol) in EtOH/H2O 3 :2 (v/v, 250 ml) was heated under reflux for 6 h. EtOH was evaporated in
vacuo, the remaining aq. phase was acidified with 1.2n HCl to pH 6. The orange solid that precipitated was
removed by filtration, washed with H2O and pentane, and finally dried in vacuo (crude yield 14.8 g (96%)). M.p.
2288. IR: 3459 (OH), 1736 (CO, acid). 1H-NMR (CDCl3): 12.4 (s, COOH); 8.65 (s, HÀC(4)); 7.45 (d, J 9,
HÀC(5)); 6.73 (dd, J 2.3, 9, HÀC(6)); 6.53 (d, J 2.3, HÀC(8)); 3.49 (q, (MeCH2)2N); 1.27 (t, (MeCH2)2N).
Anal. calc. for C14H15NO4: C 64.36, H 5.79, N 5.36; found: C 64.53, H 6.01, N 5.56.
7-(Diethylamino)-N-(5-hydroxypentyl)-2-oxo-2H-[1]benzopyran-3-carboxamide (5). To a soln. of 4 (7.8 g,
30 mmol) in CH2Cl2 at 08 were added HOBT (4.8 g, 36 mmol) in DMF (10 ml) and DCCI (6.2 g, 30 mmol) in
CH2Cl2 (15 ml). The mixture was stirred for 0.5 h at r.t. under N2. A soln. of 5-aminopentanol (3.1 g, 30 mmol)
in CH2Cl2 (6 ml) was added dropwise, and the mixture was stirred for 24 h at r.t. Dicyclohexylurea was removed
by filtration and washed with a small amount of CH2Cl2. The solvents were evaporated, and the residue was
purified by chromatography (AcOEt/CH2Cl2 1 :3 (v/v)): 9.3 g (91%) of 5. M.p. 2128. IR: 3333 (OH), 2974
(NH), 1702 (CO, amide). 1H-NMR (CDCl3): 8.84 (m, NH); 8.70 (s, HÀC(4)); 7.43 (d, J 8.76, HÀC(5)); 6.65
(dd, HÀC(6)); 6.50 (d, HÀC(8)); 4.22 (m, CH2OH); 3.67 (t, CH2NH); 3.46 (m, (MeCH2)2N, OH); 1.65 (m,
(CH2)3CH2OH); 1.29 (t, (MeCH2)2N). Anal. calc. for C19H26N2O4: C 65.89, H 7.51, N 8.09; found: C 65.06, H
7.38, N 8.53.
N-(5-Bromopentyl)-7-(diethylamino)-2-oxo-2H-[1]benzopyran-3-carboxamide (6). To 5 (4.8 g, 14 mmol),
dissolved in CH2Cl2 (25 ml) under N2, at r.t., was added CBr4 (6.5 g, 19.6 mmol). After stirring for 10 min, the
soln. was cooled to 08, and PPh3 (10.3 g, 39.2 mmol) was added. The mixture was stirred 1 h at 08, then 2 h at r.t.
After concentration of the solvent, the mixture was filtered through silica gel (CH2Cl2) to eliminate the
undesired by-products. Evaporation of the solvent provided 6 (5.1 g, 90%). M.p. 1488. 1H-NMR (CDCl3): 8.83
(m, NH); 8.71 (s, HÀC(4)); 7.44 (d, J 8.77, HÀC(5)); 6.65 (dd, J 8.77, 2.92, HÀC(6)); 6.50 (d, J 2.92,
HÀC(8)); 3.44 (m, (MeCH2)2N, NHCH2, CH2Br); 1.91 (m, CH2CH2Br); 1.58 (m, (CH2)2CH2CH2Br); 1.24 (t,
(MeCH2)2N). Anal. calc. for C19H25BrN2O3: C 55.74, H 6.11, N 6.84, Br 19.54; found: C 55.80, H 6.22, N 6.89, Br
18.95.
7-(Diethylamino)-N-{5-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]pentyl}-2-oxo-2H-[1]benzopyran-
3-carboxamide (7). A slurry of 2 (213 mg, 1 mmol), 6 (409 mg, 1 mmol), and K2CO3 (208 mg, 1.5 mmol) in 5 ml
DMF was stirred at r.t. for 72 h. H2O was added to the mixture, until all the salts were dissolved, and the soln.
was extracted with CH2Cl2. The org. phase was dried (MgSO4), filtered, and evaporated to dryness to give crude
compound. Chromatography on silica gel (AcOEt/CH2Cl2 1:3 (v/v)) gave 7 (405 mg, 75%). Light yellow solid.
M.p. 1688. IR: 3386 (OH). 1H-NMR (CDCl3): 8.82 (m, NH); 8.70 (s, HÀC(4) of Cou); 7.56 (s, 1 arom. H); 7.43
(d, J 8.76, HÀC(5) of Cou); 7.29 (s, 1 arom. H); 6.65 (dd, HÀC(6) of Cou); 6.50 (d, HÀC(8) of Cou); 5.56 (m,
CH(Me)OH); 4.09 (t, ArOCH2); 3.98 (s, MeO); 3.46 (m, (MeCH2)2N, NHCH2); 2.35 (m, CH(Me)OH); 1.92
(m, ArOCH2CH2); 1.68 (m, NHCH2(CH2)2); 1.56 (d, CH(Me)OH); 1.27 (t, (MeCH2)2N). Anal. calc. for
C28H35N3O8: C 62.10, H 6.28, N 7.76; found: C 62.15, H 6.56, N 7.66.
5'-O-{[1-(4-{5-[7-(Diethylamino)-2-oxo-2H-[1]benzopyran-3-carboxamido]pentyloxy}-5-methoxy-2-nitro-
phenyl)-ethoxy]carbonyl}thymidine (8). Compound 7 (640 mg, 1.2 mmol) and pyridine (94 mg, 96 ml, 1.2 mmol)
in 20 ml of CH2Cl2 was added dropwise under N2 to bis(trichloromethyl) carbonate (118 mg, 0.4 mmol) in 2 ml
CH2Cl2 cooled at 08. After the mixture was stirred for 4 h, thymidine (291 mg, 1.2 mmol; co-evaporated three