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M. Weitman et al. / European Journal of Medicinal Chemistry 46 (2011) 447e467
J ¼ 7.5 Hz, 3H), 1.58 (sext, J ¼ 7.2 Hz, 2H), 1.94 (quint, J ¼ 6 Hz, 2H),
3.10 (br t, J ¼ 7.5 Hz, 2H), 3.48, 3.59 (two t, J ¼ 6.3 Hz, 2H). 13C NMR
5.1.18. 4-Chloro-2,5-dipropoxyaniline, 8c [52]
Compound 8c was obtained as a brown oil in quantitative yield
(75 MHz, D2O)
d
10.3, 22.6, 27.2, 38.2, 68.2, 73.3. MS (CIþ) m/z (%):
from 7c (Procedure 4, solvent MeOH). 1H NMR (300 MHz, acetone-
118.13 (MHþ, 100). HRMS: calcd. for C6H16NO 118.1232 found
118.1279.
d6)
d
1.022, 1.025 (two t, J ¼ 8 Hz, 3H), 1.763, 1.768 (two sext,
J ¼ 7.2 Hz, 2H), 3.87, 3.90 (two t, J ¼ 6.3 Hz, 2H), 5.8 (br t, 2H), 6.69 (s,
1H), 6.82 (s, 1H). 13C NMR (75 MHz, CDCl3)
71.9, 103.4, 113.5, 114.7, 136.5, 141.9, 149.8.
d 10.8, 23.1, 23.3, 71.7,
5.1.12. 1-Isothiocyanato-3-propoxypropane, 4
Compound 4 was obtained as an orange oil in 48% yield from 3
(Procedure 5). NMR data assignment was aided by several two-
dimensional spectra including COSY, HMQC and HMBC analyses. 1H
5.1.19. 1-Chloro-4-isothiocyanato-2,5-dimethoxybenzene, 9a
Compound 9a was obtained as a bright yellow solid in quanti-
tative yield from 8a (Procedure 5, reflux in CHCl3 4.5 h, recrystal-
lized from EtOAc:hexane), mp 88-87 ꢂC, 1H NMR (300 MHz,
NMR (600 MHz, acetone-d6)
d
0.79 (t, J ¼ 7.2 Hz, 3H), 1.44 (sext,
J ¼ 7.2 Hz, 2H), 1.83 (quint, J ¼ 6 Hz, 2H), 3.26 (t, J ¼ 6.6 Hz, 2H), 3.40
(t, J ¼ 6 Hz, 2H), 3.59 (t, J ¼ 6.6 Hz, 2H). 13C NMR (150 MHz, acetone-
acetone-d6)
(50 MHz, acetone-d6) d 56.5, 56.6, 109.2, 113.7, 119.3, 121.2, 141.1,
d
3.86, 3.93 (two s, 3H) 7.03 (s, 1H), 7.19 (s, 1H). 13C NMR
d6)
d
10.8, 23.4, 30.7, 42.7, 67.2, 73.0, 130.0.
148.7, 150.1. MS (CIþ) m/z 232.00 (MHþ, 35.585), 230.00 (MHþ, 100).
HRMS: calcd. for C9H9NO2S35Cl 230.0043 found 230.0032, calcd. for
C9H9NO2S37Cl 232.0013 found 232.0007.
5.1.13. 2-Chloro-1,4-diethoxybenzene, 6b [49]
Compound 6b was obtained as a brown oil in 89% yield from 5b
(Procedure 2, solvent acetone). 1H NMR (300 MHz, acetone-d6)
d
1.33, 1.38 (two t, J ¼ 6.9 Hz, 3H), 3.84, 4.00 (two sext, J ¼ 6.9 Hz,
5.1.20. 1-Chloro-2,5-diethoxy-4-isothiocyanatobenzene, 9b
2H), 6.76 (dd, J ¼ 6.9 Hz, 3 Hz, 1H), 6.91 (d, J ¼ 9 Hz, 1H), 6.95 (d,
Compound 9b was obtained as a white solid in 40% yield from
8b (Procedure 5, solvent EtOAc, chromatography eluent 2.5:1
hexane:CH2Cl2), mp 69e72 ꢂC 1H NMR (300 MHz, acetone-d6)
J ¼ 9 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d 15.1, 15.11, 64.5, 65.8, 114.2,
115.6, 117.1, 123.7, 149.3, 153.9. MS (CIþ) m/z 201.07 (MHþ, 52.1),
200.06 (Mþ, 85.8), 173.04 (MHþ ꢀ C2H4, 43.4), 172.03 (Mþ ꢀ C2H4,
54.2), 144.00 (Mþ ꢀ 2C2H4, 100). HRMS: calcd. for C10H13O2Cl
200.0604 found 200.0610.
d
1.38,1.42 (two t, J ¼ 6.9 Hz, 3H), 4.04 4.10 (two sext, J ¼ 6.9 Hz, 2H),
6.85, 7.07 (s, 1H, s, 1H). 13C NMR (75 MHz, CDCl3)
d 14.87, 14.9, 66.0,
66.2, 111.1, 115.4, 120.1, 122.4, 142.5, 149.0, 150.56. MS (CIþ) m/z
257.03 (Mþ, 100), HRMS: calcd. for C11H12NO2S35Cl 257.0277 found
257.0266, calcd. for C11H12NO2S37Cl 259.0248 found 259.0243.
5.1.14. 2-Chloro-1,4-dipropoxybenzene, 6c
Compound 6c was obtained as a brown oil in 87% yield from 5c
(Procedure 2, solvent acetone). 1H NMR (300 MHz, acetone-d6)
5.1.21. 1-Chloro-4-isothiocyanato-2,5-dipropoxybenzene, 9c
Compound 9c was obtained as a white-pink solid in 59% yield
from 7c (Procedure 5, solvent EtOAc, chromatography eluent hex-
ane:CH2Cl2 2:1), mp 36e39 ꢂC, 1H NMR (300 MHz, acetone-d6)
d
1.00, 1.04 (two t, J ¼ 7.5 Hz, 3H), 1.77 (m, 4H), 3.88, 3.93 (two t,
J ¼ 6.6 Hz, 2H), 6.82 (m, 1H), 6.97 (m, 2H). 13C NMR (75 MHz, CDCl3)
d
10.73, 10.8, 23.22, 23.3, 70.7, 71.8, 114.5, 115, 117.2, 123.8, 149.6,
154.28. MS (CIþ) m/z 228.09 (Mþ, 42.9), 186.1 (Mþ-Prþ, 25.5), 144.0
(Mþ ꢀ 2Prþ, 100), HRMS: calcd. for C12H17O2Cl 228.0917 found
228.0942.
d
1.03, 1.08 (two t, J ¼ 7. 5 Hz, 3H), 1.81 (m, 4H), 3.97, 4.05 (two t,
J ¼ 6.3 Hz, 2H), 6.39 (s, 1H), 7.14 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
9.9, 10.0, 22.3, 71.16, 71.18, 110.5, 114, 121.8 (4ary), 148.4 (4ary), 150.1
(4ary). At the concentration of the sample, the 4ary carbons were not
observed. MS (CIþ) m/z 286.07 (MHþ, 66.2), 285.06 (Mþ, 77.8),
244.02 (MHþ ꢀ C3H6, 100), 200.96 (Mþ ꢀ 2C3H6, 49.6), HRMS:
calcd. for C13H16NO2SCl 285.059 found 285.0599.
5.1.15. 1-Chloro-2,5-diethoxy-4-nitrobenzene, 7b [44]
Compound 7b was obtained as a yellow-brown solid in 78%
yield from 6b (Procedure 3, solvent CH2Cl2), mp 96e98 ꢂC. NMR
data assignment was aided by several two-dimensional spectra
including COSY, HMQC and HMBC analyses. 1H NMR (600 MHz,
5.1.22. 1-(4-Chloro-2,5-diethoxyphenyl)-3-(3-propoxypropyl)
thiourea, 10b
acetone-d6)
d
1.38, 1.42 (two t, J ¼ 7.5 Hz, 3H), 4.18, 4.22 (two t,
J ¼ 7.2 Hz, 2H), 7.40 (s, 1H), 7.56 (s, 1H). 13C NMR (75 MHz, CDCl3)
Compound 10b-I was obtained as a colorless oil in 81% yield from
8b (Procedure 6, solvent EtOH, chromatography eluent 2.5:1 hex-
d
14.8, 66.4, 67.0, 110.7, 118.2, 128.7, 139.6, 146.8, 148.8. MS (CIþ) m/z
246.1 (MHþ, 50.9), 245.1 (Mþ, 68.49), 215.1 (Mþ ꢀ Et, 25.2), 189.0
(Mþ ꢀ 2Et, 100). HRMS: calcd. for C10H12NO4Cl 245.455 found
245.0478.
ane:CH2Cl2). 1H NMR (300 MHz, acetone-d6)
d
0.84 (t, J ¼ 7 Hz, 3H),
1.35, 1.39 (two t, J ¼ 7.2 Hz, 3H), 1.46 (sext, J ¼ 7 Hz, 2H), 1.86 (quint,
J ¼ 6.3 Hz, 2H), 3.30 (t, J ¼ 6.6 Hz, 2H), 3.48 (t, J ¼ 6 Hz, 2H), 3.67 (sext,
J ¼ 6.6 Hz, 2H), 4.07, 4.08 (two sext, J ¼ 7.0 Hz, 2H), 7.04 (s, 1H), 7.50
(br t,1H), 7.85 (br t,1H), 8.25 (br t,1H).13C NMR (50 MHz, acetone-d6)
5.1.16. 1-Chloro-4-nitro-2,5-dipropoxybenzene, 7c [50]
Compound 7c was obtained as a yellow solid in 85% yield from
6c (Procedure 3, solvent CH2Cl2, chromatography eluent CH2Cl2),
d 10.8, 15.0, 23.4, 28.6, 29.6, 43.5, 65.7, 69.5, 73.0, 111.9, 115.4, 118.6,
128.5, 145.9, 148.8, 181.7. MS (CIþ) m/z 357.15 (MHþ, 100), 329.11
(MHþ ꢀ E1tOH, 29.8). HRMS: calcd. for C17H28N2O3S35Cl 357.1509
found 357.1528, calcd. for C17H28N2O3S37Cl 377.1480 found 377.1497.
mp 79e83 ꢂC 1H NMR (300 MHz, acetone-d6)
d
1.03, 1.06 (two t,
J ¼ 7.5 Hz, 3H), 1.83 (m, 4H), 4.09, 4.12 (two t, J ¼ 6.6 Hz, 2H), 7.4 (s,
1H), 7.57 (s, 1H). 13C NMR (75 MHz, CDCl3)
d 10.6, 10.65, 23.1, 72.3,
72.7, 110.8, 118.0, 128.9, 134.2, 147.1 (4ary), 148.9 (4ary). MS (CIþ) m/z
247.08 (MHþ, 82.1). HRMS: calcd. for C12H17NO345Cl 274.0846 found
274.0819, calcd. for C12H17NO347Cl 276.0817 found 276.0786.
5.1.23. 1-(4-Chloro-2,5-dipropoxyphenyl)-3-(3-propoxypropyl)
thiourea, 10c-I
Compound 10c-I was obtained as a colorless oil in 81% yield
from 8c (Procedure 6, solvent EtOH, chromatography eluent 1:1
CH2Cl2:hexane till all the isothiocyanate was eluted, then pure
5.1.17. 4-Chloro-2,5-diethoxyaniline, 8b [51]
Compound 8b was obtained as a white solid from 7b (Procedure
4, solvent MeOH, chromatography eluent 2:1 hexane:CH2Cl2), mp
CH2Cl2). 1H NMR (300 MHz, acetone-d6)
d
0.67 (t, J ¼ 7.35 Hz, 3H),
0.97, 1.00 (two, J ¼ 7.5 Hz, 3H), 1.20 (sext, J ¼ 6.3 Hz, 2H), 1.76 (m,
6H), 3.15 (t, J ¼ 6.6 Hz, 2H), 3.45 (t, J ¼ 5.4 Hz, 2H), 3.67 (br sext,
J ¼ 5.4 Hz, 2H), 3.84, 3.86 (two t, J ¼ 6.6 Hz, 2H), 6.90 (s, 1H), 7.11 (br
69e72 ꢂC 1H NMR (300 MHz, acetone-d6)
d 1.38, 1.42 (two t,
J ¼ 7.2 Hz, 3H), 3.96, 3.99 (two sext, J ¼ 6.9 Hz, 2H), 4.51 (br t, 2H),
6.52 (s, 1H), 6.82 (s, 1H). 13C NMR (75 MHz, CDCl3)
102.3, 113.4, 114.8, 138.7, 141.3, 149.9.
d
15.2, 65.4, 65.7,
q, 1H), 7.55 (br t, 1H). 13C NMR (75 MHz, CDCl3)
d 10.3, 10.5, 22.3,
22.5, 28.4, 45.4, 70.3, 71.2, 71.3, 73.0, 110.8, 115, 120.2, 125.0, 145.6,