8736
E. Convers et al. / Tetrahedron 60 (2004) 8729–8738
(m, 2H); 3.27 (m, 2H); 1.74 (m, 2H); 1.61 (m, 2H); 1.51 (m,
1H); 1.28–1.02 (m, 5H). 13C NMR (100 MHz, d6-DMSO)
d: 166.88, 157.51, 155.04, 154.62, 149.31, 147.56, 143.40,
137.51, 130.24, 129.56, 127.62, 125.63, 124.93, 124.23,
121.12, 116.09, 47.77, 45.56, 33.26, 30.65, 25.25, 24.48.
MS (ESþ) m/z: 418 (MþHþ). IR: 3241, 2927 (NH), 1627
. LC-AccMass: calcd for C24H27N5O2:
1.60 (bs, 1H, NH). 13C NMR (100 MHz, CDCl3) d: 132.42,
130.07, 129.92, 128.51, 128.39, 128.28, 128.08, 127.75,
52.12, 50.41, 36.18, 30.87. MS (ESþ) m/z: 253 (MþHþ).
IR: 2930, 2781 (NH), 1619 (CvN) cm21. LC-AccMass:
calcd for C17H20N2: 252.163. Found (MþH)þ: 253.17
(20.6 mDa).
(CvO) cm21
417.216. Found (MþH)þ: 418.22 (þ0.4 ppm).
4.1.9. Amide 13. To a solution of 2-(2-pyridinyl)-4-
carboxyquinoline 8 (200 mg, 0.8 mmol) in 4 mL of DMF
were successively added protected N-methyl-1,3-propane-
diamine 12 (222 mg, 0.88 mmol, 1.1 equiv.), EDC (169 mg,
0.88 mmol, 1.1 equiv.) and HOBt (119 mg, 0.88 mmol,
1.1 equiv.). The reaction mixture was stirred at rt for 20 h,
then diluted with DCM and washed three times with water.
Drying on Na2SO4, filtration and evaporation gave the crude
material. Purification by chromatography on silica gel (1:4
hexane/EtOAc as eluent) gave the product. Yield: 318 mg
(100%). 1H NMR (400 MHz, CDCl3) d: 8.70–6.80 (m,
19H); 3.72 (t, J¼7.36 Hz, 2H, –CH2–CH2–CH2–); 3.49 (t,
J¼6.77 Hz, 2H, –CH2–CH2–CH2–); 3.18 (s, 3H, CH3);
3.04 (m, 2H, –CH2–CH2–CH2–). MS (ESþ) m/z: 485
(MþHþ).
4.1.6. Thiourea 11b. To a solution of the bipyridyl bound
amine hydrochloride salt 3 (1 g, 3.04 mmol) in 50 mL of
DCM was added cyclohexylisothiocyanate (475 ml,
3.34 mmol, 1.1 equiv.) and triethylamine (940 ml,
6.69 mmol, 2.2 equiv.). The reaction mixture was stirred
at rt for 24 h, then washed with water, dried over MgSO4
and evaporated. Purification by trituration in hexane
gave the product. Yield: 856 mg (65%). 1H NMR
(400 MHz, d6-DMSO) d: 9.00 (t, J¼5.12 Hz, 1H); 8.78
(m, 1H); 8.62 (m, 2H); 8.20 (2£d, J¼8.28 Hz, 2H); 8.05
(ddd, J¼7.75, 7.75, 1.67 Hz, 1H); 7.86 (ddd, J¼8.37, 7.00,
1.33 Hz, 1H); 7.68 (ddd, J¼8.16, 7.16, 1.07 Hz, 1H); 7.57
(ddd, J¼7.46, 4.80, 1.10 Hz, 1H); 7.43 (bs, 2H, NH); 3.67
(m, 2H); 3.53 (m, 2H); 1.85 (m, 2H); 1.67–1.53 (m, 3H);
1.31–1.10 (m, 5H). 13C NMR (100 MHz, d6-DMSO) d:
167.04, 155.01, 154.60, 149.32, 147.58, 143.16, 137.53,
130.27, 129.57, 127.65, 125.63, 124.96, 124.21, 121.11,
116.21, 32.23, 30.66, 25.13, 24.53, 22.02. MS (ESþ) m/z:
4.1.10. Amine 14. To a solution of amide 13 (2.36 g,
4.88 mmol) in 50 mL of DCM and 50 mL of THF were
added 8 mL of water and 8 mL of TFA. The reaction
mixture is stirred at rt for 2 h. After evaporation of the
solvents, the crude material was taken in water and washed
three times with TBME. The aqueous phase was then
poured into a saturated bicarbonate solution, then extracted
with DCM and dried with K2CO3. Evaporation and drying
under high vacuum gave the product. Yield: 1.39 g (89%).
1H NMR (400 MHz, CDCl3) d: 8.72 (m, 1H); 8.66 (m, 1H);
8.52 (m, 1H); 8.20 (m, 1H); 7.92–7.72 (m, 3H); 7.59 (m,
1H); 7.38 (m, 1H); 3.79 (t, J¼7.04 Hz, 1H); 3.25 (m, 2H);
2.97–2.84 (m, 5H); 2.49 (m, 1H); 1.91 (m, 1H); 1.66 (m,
1H). 13C NMR (100 MHz, CDCl3) d: 168.71, 155.88,
155.65, 149.18, 148.14, 143.60, 137.01, 130.33, 130.15,
127.80, 124.85, 124.61, 124.34, 121.79, 115.86, 39.23,
36.64, 36.48, 31.43. MS (ESþ) m/z: 321 (MþHþ). IR: 3306,
2929 (NH), 1628 (CvO) cm21. LC-AccMass: calcd for
C19H20N4O: 320.164. Found (MþH)þ: 321.17 (20.5 mDa).
434 (MþHþ). IR: 3239, 2929 (NH), 1646 (CvO) cm21
(MþH)þ: 434.20 (þ0.3 ppm).
.
LC-AccMass: calcd for C24H27N5OS: 433.194. Found
4.1.7. Carbodiimide 6. To a solution of the thiourea 11b
(100 mg, 0.23 mmol) in 8 mL of DMF were added the
polymer-supported Mukaiyama’s reagent (892 mg,
10 equiv.) and triethylamine (64 ml, 0.46 mmol, 2 equiv.).
The reaction mixture was agitated in a FlexChem oven at
45 8C for 4 h. The resin was then filtered and washed with
DMF, MeOH (3 times). After evaporation, the residue was
taken in 5 mL of DCM. 750 mg of carbonate resin
(previously washed with DCM) was added and the mixture
was stirred at rt for 1 h. Filtration and evaporation gave the
1
product. Yield: 19 mg (21%). H NMR (400 MHz, CDCl3)
d: 8.73 (m, 1H); 8.67 (m, 2H); 8.34 (dd, J¼8.46, 0.87 Hz,
1H); 8.21 (m, 1H); 7.90 (ddd, J¼7.73, 7.73, 1.83 Hz, 1H);
7.78 (ddd, J¼8.37, 6.91, 1.42 Hz, 1H); 7.62 (ddd, J¼8.37,
6.95, 1.33 Hz, 1H); 7.39 (ddd, J¼7.48, 4.78, 1.17 Hz, 1H);
6.61 (bs, 1H, NH); 3.72 (m, 2H); 3.59 (m, 2H); 1.88–1.83
(m, 2H); 1.64–1.59 (m, 2H); 1.48 (m, 1H); 1.31–1.10 (m,
5H). IR: 3267, 2926 (NH), 2116 (NvCvN), 1649
4.1.11. Urea 15a. To a solution of the bipyridyl bound
amine 14 (200 mg, 0.62 mmol) in 10 mL of DCM was
added cyclohexylisocyanate (88 ml, 0.69 mmol, 1.1 equiv.)
and triethylamine (95 ml, 0.69 mmol, 1.1 equiv.). The
reaction mixture was stirred at rt for 24 h. The reaction
mixture was washed with water, dried on MgSO4 and
evaporated. Purification by chromatography on silica gel
(with MeOH 3% in DCM as eluent) gave the product. Yield:
(CvO) cm21
.
1
4.1.8. Protected amine 12. To a solution of N-methyl-1,3-
propanediamine (500 mg, 5.67 mmol) in 10 mL of DCM
was added benzophenone imine (950 ml, 5.67 mmol,
1 equiv.) under inert atmosphere. The reaction mixture
was stirred at rt for 24 h, and then diluted with 20 mL of
DCM. Three washes with a 1% bicarbonate solution
followed by drying over MgSO4 and evaporation gave the
product as a yellow oil. Yield: 1.36 g (95%). 1H NMR
(400 MHz, CDCl3) d: 7.59 (m, 2H); 7.39 (m, 6H); 7.16 (m,
2H); 3.43 (t, J¼6.82 Hz, 2H, –CH2–CH2–CH2–); 2.66 (t,
J¼7.04 Hz, 2H, –CH2–CH2–CH2–); 2.42 (s, 3H, CH3);
1.87 (ddd, J¼13.95, 6.95, 6.95 Hz, 2H, –CH2–CH2–CH2–);
260 mg (94%). H NMR (400 MHz, CDCl3) d: 8.70 (m,
2H); 8.55 (m, 1H); 8.22 (m, 1H); 7.99–7.74 (m, 3H); 7.61
(m, 1H); 7.48–7.38 (m, 1H); 5.62 (bs, 1H, NH); 4.08 (m,
1H); 3.79 (m, 1H); 3.52–3.38 (m, 2H); 3.24 (s, 3H, Me);
1.92 (m, 4H); 1.73–1.49 (m, 3H); 1.42–1.10 (m, 4H). MS
(ESþ) m/z: 445 (MþHþ).
4.1.12. Thiourea 15b. To a solution of the bipyridyl bound
amine 14 (1.2 g, 3.76 mmol) in 60 mL of DCM was added
cyclohexylisothiocyanate (800 ml, 5.64 mmol, 1.5 equiv.).
The reaction mixture was stirred at rt for 30 h, then washed
with water, dried on MgSO4 and evaporated. Purification by