L. J. Crane et al. / Tetrahedron 60 (2004) 5325–5330
5329
4.1.6. 3-Fluoro-4-(2-acetamidoethylamino)-benzonitrile
(2h0). 3-Fluoro-4-(2-aminoethylamino)-benzonitrile 2h
(3.22 g, 0.02 mol) in acetic anhydride (25 mL) was heated
under reflux with stirring in an oil bath for 5 h. The reaction
mixture was then cooled, and the anhydride was removed
under reduced pressure. The crude product was washed with
water, collected by filtration and purified on silica gel
column using as eluent AcOEt/CH2Cl2 (1:1). 1H NMR
(DMSO-d6) d: 1.90 (s, 3H, CH3), 3.31–3.48 (m, 4H, 2CH2),
6.73 (s, 1H, PhNH), 6.92–7.67 (m, 3H, ArH), 8.15 (s, 1H,
CONH). IR (KBr, cm21) 1635 (nCO), 2247 (nCN), 2975
(nCH2CH3), 3081 (nCH), 3251 and 3395 (nNH). Elemental
analysis calculated for C11H12FN3O: C, 59.72; H, 5.47; N,
18.99; found: C, 59.53; H, 5.54; N, 19.06.
or by column chromatography with ethyl acetate/ethanol
(1:1) as eluent. All imidazoline compounds present the same
IR absorption bands towards 3000 cm21 (nCH, CH2) and
3150 cm21 (nNH).
NMR data of compounds 4a12, 4b38, 4c39, 4d40, 4e40, 4f41
and 4i12 are in agreement with literature data.
4.3.1. 2-(20,40-Difluorophenyl)-4,5-dihydro-1H-imidazole
1
(4g). H NMR (CDCl3) d: 3.76 (s, 4H, CH2CH2), 5.03 (s,
1H, NH), 6.89 (m, 2H, H5, H6), 8.08 (m, 1H, H3). Elemental
analysis calculated for C9H8F2N2: C, 59.34; H, 4.43; N,
15.38; found: C, 59.28; H, 4.55; N, 15.23.
4.3.2. 2-(30,40-Difluorophenyl)-4,5-dihydro-1H-imidazole
1
4.2. General procedure for thioamides 3
(4h). H NMR (CDCl3) d: 3.78 (s, 5H, CH2CH2 and NH),
7.17 (m, 1H, H5), 7.49 (m, 1H, H6), 7.61 (m, 1H, H2).
Elemental analysis calculated for C9H8F2N2: C, 59.34; H,
4.43; N, 15.38; found: C, 59.31; H, 4.38; N, 15.52.
An appropriate aromatic halogenated nitrile 1 (about
0.03 mol) was dissolved in pyridine (20 mL), then triethyl-
amine (0.033 mol, 5 mL) and ammonium sulfide 20 % wt
solution in water (0.033 mol, 10 mL) were added into the
mixture at 50 8C for 3–6 h. After cooling, the mixture was
diluted with cold water (50 mL). The precipitated solid was
filtered off, washed with cold water and crystallized from
cyclohexane or purified by column chromatography with
dichloromethane as eluent.
Acknowledgements
This work was carried out with the technical support of
Mr L. Amielet. The authors thank the Laboratoires Servier
for their support and particularly Mr D. H. Caignard and
Mr P. Renard.
NMR data of compounds 3a,33 3b,34 3c,35 3d,28 3e,34 3f,36
3j30 and 3k37 are in agreement with literature data.
1
4.2.1. 2,4-Difluorothiobenzamide (3g). H NMR (CDCl3)
References and notes
d: 6.86 (m, 1H, H5), 6.99 (m, 1H, H3), 7.76 and 8.04 (2s
broad, 2H, NH2), 8.46 (m, 1H, H6) IR (KBr, cm21): 3366,
3292 (nNH2), 3167 (nCH), 1630, 1602 (nCvC), 1283
(nCvS). Elemental analysis calculated for C7H5F2NS: C,
48.55; H, 2.91; N, 8.09; S, 18.51; found: C, 48.52; H, 3.09;
N, 7.92; S, 18.23
1. Schorderet, M. In Pharmacologie: Des Concepts Fonda-
´
mentaux aux Applications Therapeutiques; Frison-Roche:
Paris, 1992; pp 130–153.
2. (a) Blancafort, P. Drugs of the Future 1978, 3, p 592.
(b) Serradell, M. N.; Castan˜er, J. Drugs of the Future 1986, 6,
p 470.
1
4.2.2. 3,4-Difluorothiobenzamide (3h). H NMR (CDCl3)
3. Wang, X.; Rondu, F.; Lamouri, A.; Dokhan, R.; Marc, S.;
Touboul, E.; Pfeiffer, B.; Manechez, D.; Renard, P.;
Guardiola-Lemaitre, B.; Godfroid, J.-J.; Ktorza, A.; Penicaud,
L. J. Pharmacol. Exp. Ther. 1996, 278, 82–89.
d: 7.11 (s broad, 2H, NH2), 7.19 (m, 1H, H5), 7.62 (m, 1H,
H6), 7.81 (m, 1H, H2) IR (KBr, cm21): 3402, 3270 (nNH2),
3155 (nCH), 1627, 1600 (nCvC), 1261 (nCvS). Elemental
analysis calculated for C7H5F2NS: C, 48.55; H, 2.91; N,
8.09; S, 18.51; found: C, 48.36; H, 2.85; N, 8.17; S, 18.62.
4. Rondu, F.; Le Bihan, G.; Wang, X.; Lamouri, A.; Touboul, E.;
Dive, G.; Bellahsene, T.; Pfeiffer, B.; Renard, P.; Guardiola-
Lemaitre, B.; Manechez, D.; Penicaud, L.; Ktorza, A.;
Godfroid, J. J. J. Med. Chem. 1997, 40, 3793–3803.
5. Pele-Tounian, A.; Wang, X.; Rondu, F.; Lamouri, A.;
Touboul, E.; Marc, S.; Dokhan, R.; Pfeiffer, B.; Manechez,
D.; Renard, P.; Guardiola-Lemaitre, B.; Godfroid, J.-J.;
Penicaud, L.; Ktorza, A. Br. J. Pharmacol. 1998, 124,
1591–1597.
4.2.3. 3-Chloro-4-fluoro-thiobenzamide (3i). 1H NMR
(CDCl3) d: 7.19 (m, 1H, H2), 7.64 (s, 2H, NH2), 7.78 (m, 1H,
H5), 7.99 (dd, 1H, H6) IR (KBr, cm21): 3442, 3206 (nNH2),
3101, 3129 (nCH), 1618 (nCvC), 1262 (nCvS). Elemental
analysis calculated for C7H5ClFNS: C, 44.34; H, 2.66;
N, 7.39; S, 16.91; found: C, 44.41; H, 2.53; N, 7.21; S,
16.88.
6. Le Bihan, G.; Rondu, F.; Pele-Tounian, A.; Wang, X.; Lidy,
S.; Touboul, E.; Lamouri, A.; Dive, G.; Huet, J.; Pfeiffer, B.;
Renard, P.; Guardiola-Lemaitre, B.; Manechez, D.; Penicaud,
L.; Ktorza, A.; Godfroid, J.-J. J. Med. Chem. 1999, 42(9),
1587–1603.
4.3. General procedure for imidazolines 4
A stirred mixture of aromatic halogenated thiobenzamides 3
(0.02 mol) and EDA in stoichiometric quantity, freshly
distilled on KOH was heated at 120 8C in an oil bath for
several days. The reaction mixture was then cooled, poured
into cold water and extracted with CH2Cl2. The organic
phase was dried over anhydrous MgSO4. The solvent was
removed under reduced pressure and the crude free base was
collected and purified by recrystallization from cyclohexane
7. Crane, L.; Anastassiadou, M.; El Hage, S.; Stigliani, J. L.;
Baziard-Mouysset, G.; Payard, M.; Bizot-Espiard, J. G.;
Caignard, D. H.; Renard, P., in preparation.
8. Chan, S. Clin. Sci. 1993, 85, 671–677.
9. Vizi, E. S. Med. Res. Rev. 1986, 6, 431.
10. Li, H. Y.; Drummond, S.; De Lucca, I.; Boswell, G. A.
Tetrahedron 1996, 52, 11153–11162.