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M. Altamura et al. / Tetrahedron 62 (2006) 6754–6761
The column was conditioned with n-hexane. Compound 7
was eluted first using 50% of CH2Cl2 in n-hexane (31 mg
as a yellow solid; yield¼10%). Compound 6 was then eluted
using 20% of ethyl acetate in n-hexane (314 mg as a white
solid; yield¼40%).
analysis was purified by chromatography on silica eluting
with ethyl acetate. Mp: 97–102 ꢁC. ESI+-MS: m/z¼479
(MH+), 305, 144. IR (KBr) n (cmꢀ1): 3400, 3288, 3047,
1
2929, 2853, 1623. H NMR (DMSO-d6, 300 K, 500 MHz):
10.82 d (1H, br s), 10.80 d (1H, br s), 10.79 d (1H, br s),
10.76 d (1H, br s), 7.60 d (1H, t), 7.44 d (1H, dd), 7.42
d (1H, t), 7.35–7.21 d (5H, m), 7.09–6.91 d (6H, m), 6.79
d (1H, m), 3.66 d (2H, m), 3.33 d (2H, m), 2.99–2.91
d (4H, m), 3.01, 3.00, 2.83 and 2.77 d (6H, singlets). 13C
NMR (DMSO-d6) d: 169.26, 169.20, 168.84, 168.80,
136.42, 136.02, 135.16, 134.87, 134.72, 134.64, 128.41,
128.33, 128.25, 128.16, 127.08, 126.86, 126.34, 126.20,
125.99, 122.71, 120.75, 118.46, 118.00, 117.94, 111.28,
111.25, 111.18, 110.68, 51.56, 47.46, 47.26, 32.01, 23.60,
22.32. HRMS (MH+) calcd for C30H31N4O2: 479.2442;
found: 479.2419.
4.1.1.1.
2-Diethylthiocarbamoyl-N,N-diethyl-benz-
amide. Compound 6. Mp: 81 ꢁC–82 ꢁC (n-hexane).
Rf ¼0.1, CH2Cl2/n-hexane, 1:1. IR (KBr) n (cmꢀ1): 2990,
2968, 2930, 2880, 2867, 1626, 1510, 1429. ESI+-MS: m/z¼
293 (MH+), 220, 192, 164, 130, 121, 105. C16H24N2OS
(292.44): calcd C, 65.71; H, 8.27; N, 9.58; found C 65.43,
1
H 8.42, N 9.44. H NMR (DMSO-d6, 300 K, 600 MHz):
7.39 d (1H, t), 7.33 d (1H, t), 7.25 d (1H, d), 7.15 d (1H,
d), 4.32 d (1H, m), 3.61 d (1H, m), 3.57 d (1H, m), 3.43
d (1H, m), 3.28 d (1H, m), 3.16 d (1H, m), 3.09 d (1H, m),
3.01 d (1H, m), 1.19 d (3H, t), 1.07 d (3H, t), 1.05 d (3H,
t), 1.04 d (3H, t). 13C NMR (CDCl3) d: 196.69, 169.38,
140.90, 132.76, 128.51, 127.23, 125.53, 124.81, 48.44,
45.46, 43.42, 38.81, 13.86, 13.45, 12.32, 10.82.
4.1.4. Synthesis of N,N0-bis-[2-(1H-indol-3-yl)-ethyl]-
N,N0-dimethyl-benzene-1,2-dicarbothioic acid. Com-
pound 9. LR (694 mg, 1.71 mmol) and amide 8 (362 mg,
0.75 mmol) were suspended in 11 ml of anhydrous toluene
under magnetic stirring and a nitrogen atmosphere. The sol-
vent was made to reflux for 1 h. During this time, a dark
orange solution formed. The volatiles were removed under
reduced pressure and the residue (1.45 g) was purified by
Flash-Master chromatography using CH2Cl2 as eluent.
Compound 9 was obtained (188 mg as a pale yellow solid,
yield¼49%) by collecting together the fractions correspond-
ing to three spots on the TLC plate: Rf¼0.17, 0.26, 0.32
(ethyl acetate/CH2Cl2, 3:97 as eluent). ESI+-MS: m/z¼511
(MH+), 337, 144. C30H30N4S2 (510.72): calcd C, 70.55; H,
4.1.1.2.
N,N,N0,N0-Tetraethyl-benzene-1,2-dicarbo-
thioic acid. Compound 7. Mp: 118 ꢁC–119 ꢁC (ethyl
acetate). Rf¼0.1, ethyl acetate/n-hexane, 1:4. IR (KBr) n
(cmꢀ1): 3076, 3058, 3007, 2974, 2953, 2872, 1507, 1429.
ESI+-MS: m/z¼309 (MH+), 236, 208, 180. C16H24N2S2
(308.51): calcd C, 62.29; H, 7.84; N, 9.08; found C 62.50,
1
H 7.99, N 9.01. H NMR (DMSO-d6, 300 K, 600 MHz):
7.25 d (2H, m), 7.08 d (2H, m), 4.60 d (2H, m), 3.70
d (2H, m), 3.46 d (2H, m), 3.29 d (2H, m), 1.29 d (6H, t,
J¼7.1 Hz), 1.14 d (6H, t, J¼7.2 Hz). 13C NMR (CDCl3)
d: 196.27, 138.38, 127.52, 124.48, 48.96, 45.12, 13.52,
10.51.
1
5.92; N, 10.97; found C 70.07, H 5.99, N 10.67. H NMR
(DMSO-d6, 300 K, 600 MHz) of the major (E,Z) conformer:
10.86 d (1H, br s), 10.83 d (1H, br s), 7.73 d (1H, d,
J¼8.0 Hz), 7.36–6.85 d (13H, m), 4.45 d (1H, m), 4.00
d (1H, m), 3.81 d (1H, m), 3.51 d (3H, s), 3.50 d (1H, m),
3.25–3.16 d (2H, m), 3.12 d (3H, s), 3.00 d (1H, m). After
the identification, 9 was renamed as mixture 9a–9c. 13C
NMR (DMSO-d6) d: 196.66, 196.54, 196.31, 196.06,
139.21, 138.70, 138.65, 138.23, 136.12, 135.98, 127.41,
127.09, 127.00, 126.82, 126.78, 124.96, 124.74, 124.40,
124.27, 122.96, 122.78, 120.87, 118.43, 118.151, 111.26,
110.84, 110.74, 110.16, 110.10, 57.47, 57.34, 54.53,
54.07, 42.42, 42.38, 23.71, 20.52. The acquisition of 13C
NMR spectrum started several hours after compound 9a
dissolution and must be considered as the spectrum of the
thermodynamic mixture 9a–9c in DMSO-d6.
4.1.2. Synthesis of compound 7 from compound 6. LR
(476 mg, 1.17 mmol) and thioxoamide
6
(292 mg,
1.0 mmol) were suspended in 8 ml of anhydrous THF under
magnetic stirring and a nitrogen atmosphere. The solvent
was refluxed for 8 h, and then the mixture was left to stand
overnight. LR (202 mg, 0.50 mmol) was added and the sol-
vent was refluxed for 3 h. LR (203 mg, 0.50 mmol) was
added and the solvent refluxed for 5 h, then the mixture
was left on standing overnight. LR (203 mg, 0.50 mmol)
was added and the solvent refluxed for 1 h. The volatiles
were removed under reduced pressure and the residue
(2.06 g) was purified by Flash-Master chromatography.
Compound 7 (188 mg as a white solid, yield¼61%) was
eluted using 50% of CH2Cl2 in n-hexane.
4.1.5. Conversion to thioamide 9a. The mixture of thio-
amides 9a–9c, obtained as described above (473 mg,
0.93 mmol) and CHCl3 (500 ml, 6.2 mmol) were placed in
a stoppered HPLC vial, which was heated at 40 ꢁC for 8 h
in a sand bath. The mixture was filtered with the help of
few milliliters of pre-cooled CHCl3. Compound 9a
(464 mg) was recovered as a white solid. Rf¼0.32 (ethyl
acetate/CH2Cl2, 3:97 as eluent). ESI+-MS: m/z¼511 (MH+),
337, 144. The composition of this solid was not altered after
standing for a few months on the shelf, at rt. On the other
hand, it melted in a capillary tube, after 30 min at 130 ꢁC.
IR (KBr) n (cmꢀ1): 3275, 3057, 3000, 2930, 2852, 1514,
1457. 1H NMR (DMSO-d6, 300 K, 600 MHz): 10.84
d (1H, br s), 8.32 d (1H, s), 7.73 d (1H, d, J¼7.9 Hz), 7.33
d (4H, m), 7.22 d (2H, s), 7.10 d (2H, dd, J¼5.6, 3.2 Hz),
4.1.3. Synthesis of N,N0-bis-[2-(1H-indol-3-yl)-ethyl]-
N,N0-dimethyl-phthalamide. Compound 8. Phthalic anhy-
dride (325 mg, 2.60 mmol) and N-methyltryptamine (1.00 g,
5.74 mmol) were dissolved in 8 ml of anhydrous DMF under
a nitrogen atmosphere. The mixture was magnetically stirred
for 1 h at rt. DIPEA (672 mg, 5.20 mmol), EDCI (598 mg,
3.12 mmol), and HOBt (422 mg, 3.12 mmol) were added
and the mixture was left overnight under stirring. The solu-
tion was poured into 1 M aqueous HCl under vigorous stir-
ring. The white precipitated material was collected by
filtration, washed with water, and dried in the air. Compound
8 (1.11 g; yield¼89%) was obtained as a white solid and
used for thionation without further purification. Rf ¼0.31
(ethyl acetate as eluent). The sample for bioassays and