Antiviral Activities of Chiral Thiourea Derivatives
J. Agric. Food Chem., Vol. 57, No. 4, 2009 1385
O,O′-Di-n-butyl isothiocyanato (phenyl) methylphosphonate (7d):
light yellow liquid; n2D5 ) 1.6362; yield, 57.8%; IR (KBr, cm-1) ν
2958.0, 2061.9, 1494.3, 1454.3, 1385.6, 1259.5, 1022.3 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.89-0.92 (6H, m, 2CH3), 1.34-1.40 (4H, m,
2CH2), 1.54-1.63 (4H, m, 2CH2), 3.94-3.99 (4H, m, 2OCH2), 4.00
(1H, d, J ) 18.02 Hz, CH), 7.37-7.43 (5H, m, ArH); 13C NMR (125
MHz,CDCl3) δ 137.24, 131.97, 128.95, 128.83, 127.49, 67.93, 67.58,
57.81, 57.40, 18.67, 13.61; 31P NMR (200 MHz, CDCl3) δ 16.02.
General Procedure for the Preparation of Title Compounds
8a-8n. A solution of O,O′-dialkyl isothiocyanato(phenyl)meth-
ylphosphonate 7 (1 mmol) in tetrahydrofuran (10 mL) was stirred,
followed by dropwise addition of chiral amine (1.2 mmol). The reaction
mixture was stirred for 0.5 h at 25 °C, the solvent was removed by
evaporation, and the crude product was purified by chromatography
on silica using a mixture of petroleum ether and ethyl acetate (2:1) as
the eluent to give the title compounds 8a-8n in 58-70% yields.
Data for O,O′-diethyl phenyl[3-((S)-1-phenylethyl) thioureido] me-
thylphosphonate (8a): white crystal, mp 97-98 °C; yield, 70%; [R]D20
) +16.8 (c 1.7, acetone); IR (KBr, cm-1) ν 3300, 3118, 3057, 2983,
1533, 1492, 1452, 1336, 1207, 1018, 763, 742, 698, 565, 542; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.31 (1H, br s, NH), 8.19 (1H, br d, J )
7.4 Hz, NH), 7.31-7.25(10H, m, ArH), 6.10 (1H, d, J ) 20.0 Hz,
N-CH-P), 5.37(1H, br s, N-CH-Ar), 3.97-3.83 (4H, m, 2OCH2),
1.38-0.98 (9H, m, 3CH3); 13C NMR (125 MHz, DMSO-d6) δ 182.7,
144.5, 136.6, 128.9, 128.7, 128.4, 128.2, 127.4, 126.5, 63.2, 53.9, 53.6,
21.5, 16.0; 31P NMR (200 MHz, D3CCOCD3) δ 22.3, 22.1. Anal. Calcd
for C20H27N2O3PS: C, 59.10; H, 6.70; N, 6.89. Found: C, 59.01; H,
6.39; N, 6.58.
O,O′-Diethylphenyl [3-((R)-1-phenylethyl) thioureido] methylphos-
phonate (8b): white crystal; mp 80-82 °C; yield, 70%; [R]2D0 ) -16.5
(c 1.6, acetone); IR (KBr, cm-1) ν 3300, 3116, 3062, 2974, 1537, 1494,
1452, 1336, 1207, 1051, 1018, 763., 742, 698, 565, 542; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.53 (1H, br s, NH), 7.88 (1H, br d, J )
7.4 Hz, NH), 7.47-7.14 (10H, m, ArH), 6.50 (1H, d, J ) 18.0 Hz,
N-CH-P), 5.5 (1H, br s, N-CH-Ar), 4.30-3.39 (4H, m, 2OCH2),
1.42-0.93 (9H, m, 3CH3); 13C NMR (D3CCO CD3, 125 MHz) δ 182.9,
143.7, 135.5, 128.9, 128.7, 128.2, 127.4, 126.7, 126.4, 64.0, 54.9, 53.6,
21.5, 16.3; 31P NMR (200 MHz, D3CCOCD3) δ 22.5, 22.4. Anal. Calcd
for C20H27N2O3PS: C, 59.10; H, 6.70; N, 6.89. Found: C, 59.35; H,
6.62; N, 6.51.
CH3), 1.42-1.37 (4H, m, 2CH2), 0.89(6H, t, J ) 5.1 Hz, 2CH3); 13C
NMR (D3CCOCD3, 125 MHz) δ 182.7, 143.2, 135.5, 128.9, 128.5,
128.1, 128.0, 126.9, 126.2, 68.6, 54.8, 53.4, 23.5, 21.8, 9.8; 31P NMR
(200 MHz, D3CCOCD3) δ 22.4, 22.3. Anal. Calcd for C22H31N2O3PS:
C, 60.81; H, 7.19; N, 6.45. Found: C, 60.67; H, 7.33; N, 6.18.
O,O′-Di-n-propylphenyl [3-((R)-1-phenylethyl) thioureido] meth-
ylphosphonate (8f): white crystal; mp 69-70 °C; yield, 67%; [R]D20
)
-15.1 (c 1.7, acetone); IR (KBr, cm-1) ν 3305 3130, 3062, 2966, 1512,
1494, 1452, 1352, 1215, 1012, 756, 698, 565, 549; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.49 (1H, br s, J ) 7.4 Hz, NH), 7.87 (1H,
br s, NH), 7.49-7.14 (10H, m, ArH), 6.46 (1H, s, N-CH-P), 5.50
(1H, br s, N-CH-Ar), 4.26-3.49 (4H, m, 2OCH2), 1.61(3H, d, J )
20.0 Hz, CH3), 1.43-1.39 (4H, m, 2CH2), 1.04 (6H, t, J ) 3.5 Hz,
2CH3); 13C NMR (D3CCOCD3, 125 MHz) δ 183.2, 143.2, 136.2, 128.9,
128.8 128.5, 128.0, 127.3, 126.5, 68.6, 54.8, 53.6, 23.3, 21.8, 9.3; 31P
NMR (200 MHz, D3CCOCD3) δ 22.8, 22.6. Anal. Calcd for
C22H31N2O3PS: C, 60.81; H, 7.19; N, 6.45. Found: C, 60.57; H, 7.31;
N, 6.28.
O,O′-Di-n-propylphenyl [3-((S)-1-cyclohexylethyl) thioureido] me-
thylphosphonate (8g): white crystal; mp 145-147 °C; yield, 62%; [R]2D0
) +14.2 (c 1.5, acetone); IR (KBr, cm-1) ν 3302, 3142, 3084, 2966,
1541, 1450, 1359, 1213, 1011, 752, 696, 563, 549; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.33 (1H, s, NH), 8.75 (1H, d, J ) 7.4 Hz,
NH), 7.35-7.34 (5H, m, ArH), 6.22 (1H, s, N-CH-P), 5.41 (1H, br
s, N-CH-cyclohexyl), 3.84-3.74 (4H, m, 2OCH2), 1.66-1.51 (11H,
cyclohexyl-H), 1.42-1.27 (4H, m, 2CH2), 1.02 (3H, d, J ) 7.2 Hz,
CH3), 0.85 (6H, t, J ) 6.4 Hz, 2CH3); 13C NMR (D3CCOCD3, 125
MHz) δ 182.6, 136.8, 128.7, 128.4, 126.7¬68.4, 68.4, 54.9, 53.7, 32.1,
28.8, 26.6, 26.2, 17.6, 10.2; 31P NMR (200 MHz, D3CCOCD3) δ 22.5,
22.4. Anal. Calcd for C22H37N2 O3PS: C, 59.97; H, 8.46; N, 6.36. Found:
C, 60.10; H, 8.39; N, 6.45.
O,O′-Di-n-propyl phenyl [3-((R)-1-cyclohexylethyl) thioureido] me-
thylphospho-nate (8h): white crystal; mp 143-145 °C; yield, 55%;
[R]2D0 ) -14.4 (c 1.6, acetone); IR (KBr, cm-1) ν 3302, 3138, 3084,
1
2966, 1541, 1450, 1359, 1213, 1010, 732, 696, 563, 549; H NMR
(D3CCOCD3, 500 MHz) δ 8.33 (1H, s, NH), 8.75 (1H, d, J ) 7.4,
NH), 7.35-7.34 (5H, m, ArH), 6.22 (1H, s, N-CH-P), 4.15 (1H, br
s, N-CH-cyclohexyl), 3.94-3.62 (4H, m, 2OCH2), 1.69-1.40 (11H,
cyclohexyl-H), 1.19-1.07 (4H, m, 2CH2), 1.04 (3H, d, J ) 22.0 Hz,
CH3), 0.86 (6H, t, J ) 3.5 Hz, 2CH3); 13C NMR (125 MHz,
D3CCOCD3) δ 182.7, 136.8, 128.7, 128.4, 126.7¬68.4, 68.4, 54.9, 53.7,
32.1, 28.8, 26.6, 26.2, 17.6, 10.3; 31P NMR (200 MHz, D3CCOCD3) δ
22.8, 22.6. Anal. Calcd for C22H37N2O3PS: C, 59.97; H, 8.46; N, 6.36.
Found: C, 59.97; H, 8.46; N, 6.36.
O,O′-Diisopropyl phenyl [3-((S)-1-phenylethyl) thioureido] meth-
ylphosphonate (8i): white crystal; mp 112-114 °C; yield, 65%; [R]D20
) +14.1 (c 2.0, acetone); IR (KBr, cm-1) ν 3305, 3116, 3062, 2980,
1541, 1454, 1375, 1338, 1205, 1012, 767, 700, 572; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.37 (1H, br s, NH), 7.87 (1H, br d, J )
7.4 Hz, NH), 7.52-7.26 (10H, m, ArH), 6.45 (1H, s, N-CH-P), 5.66
(1H, br s, N-CH-Ar), 4.68-4.67 (2H, m, 2OCH), 1.25 (3H, d, J )
6.0 Hz, CH3), 1.15 (12H, d, J ) 6.3, 4CH3); 13C NMR (125 MHz,
DMSO-d6) δ 183.4, 144.1, 136.5, 128.7, 128.4, 128.3, 127.8, 126.9,
126.2, 72.7, 55.4, 53.0, 23.8, 22.7; 31P NMR (200 MHz, D3CCOCD3)
δ 21.0, 20.8. Anal. Calcd for C22H31N2O3PS: C, 60.81; H, 7.19; N,
6.45. Found: C, 60.89; H, 7.20; N, 6.77.
O,O′-Diisopropyl phenyl [3-((R)-1-phenylethyl) thioureido] meth-
ylphosphonate (8j): white crystal; mp 113-114 °C; yield, 67%; [R]D20
) -14.1 (c 1.8, acetone); IR (KBr, cm-1) ν 3305, 3116, 3062, 2980,
1541, 1494, 1452, 1338, 1205, 1014, 767, 700, 572; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.44 (1H, br s, NH), 7.92 (1H, br d, J )
7.4 Hz, NH), 7.35-7.26 (10H, m, ArH), 6.43 (1H, s, N-CH-P), 5.66
(1H, br s, N-CH-Ar), 2.86-2.81 (2H, m, 2OCH), 1.25 (3H, d, J )
5.0 Hz, CH3), 1.15 (12H, d, J ) 5.3, 4CH3); 13C NMR (125 MHz,
DMSO-d6) δ 183.1, 143.7, 136.5, 128.7, 128.4, 128.3, 127.8, 126.9,
126.1, 72.8, 55.8, 53.1, 23.7, 22.6; 31P NMR (200 MHz, D3CCOCD3)
δ 21.0, 20.8. Anal. Calcd for C22H31N2O3PS: C, 60.81; H, 7.19; N,
6.45. Found: C, 60.86; H, 7.39; N, 6.75.
O,O′-Diethylphenyl [3-((S)-1-cyclohexylethyl)thioureido]methylphos-
phonate (8c): white crystal; mp 134-135 °C; yield, 60%; [R]2D0 ) +15.3
(c 1.3, acetone); IR (KBr, cm-1) ν 3319, 3124, 3078, 2978, 1541, 1492,
1454, 1354, 1207, 1031, 763., 742, 696, 565, 543; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.19 (1H, br s, NH), 7.64 (1H, bs d, J )
7.4 Hz, NH), 7.34-7.25 (5H, m, ArH), 6.16 (1H, d, J ) 13.0 Hz,
N-CH-P), 4.11(1H, br s, N-CH-cyclohexyl), 4.00-3.69 (4H, m,
2OCH2), 1.16-1.00 (11H, m, cyclohexyl-H), 1.38-0.98 (9H, m,
3CH3); 13C NMR (D3CCOCD3, 125 MHz) δ 182.7, 136.8, 128.7, 128.4,
128.2, 63.1, 62.8, 54.5, 54.3, 28.8, 26.3, 26.2, 16.7, 16.5; 31P NMR
(200 MHz, D3CCOCD3) δ 22.6, 22.5. Anal. Calcd for C20H33N2O3PS:
C, 58.23; H, 8.06; N, 6.79. Found: C, 58.11; H, 8.05; N, 6.56.
O,O′-Diethyl phenyl [3-((R)-1-cyclohexylethyl) thioureido] meth-
ylphosphonate (8d): white crystal; mp 136-137 °C; yield, 65%; [R]D20
) -15.6 (c 1.4, acetone); IR (KBr, cm-1) ν 3321, 3124, 3078, 2976,
1541, 1492, 1454, 1354, 1207, 1031, 763, 742, 698, 565, 545; 1H NMR
(D3CCOCD3, 500 MHz) δ 8.24 (1H, br s, NH), 7.64 (1H, br d, J )
7.4 Hz, NH), 7.37-7.31 (5H, m, ArH), 6.21 (1H, d, J ) 21.0 Hz,
N-CH-P), 4.11 (1H, br s, N-CH-cyclohexyl), 4.03-3.75 (4H, m,
2OCH2), 1.20-1.03 (11H, m, cyclohexyl-H), 1.69-0.96 (9H, m,
3CH3); 13C NMR (D3CCOCD3, 125 MHz) δ 182.7, 136.8, 128.8, 128.4,
128.0, 62.8, 54.5, 54.3, 42.9, 29.2, 26.3, 26.2, 16.8, 16.7; 31P NMR
(200 MHz, D3CCOCD3) δ 22.5, 22.7. Anal. Calcd for C20H33N2O3PS:
C, 58.23; H, 8.06; N, 6.79. Found: C, 58.34; H, 8.18; N, 6.60.
O,O′-Di-n-propyl phenyl [3-((S)-1-phenylethyl) thioureido] meth-
ylphosphonate (8e): white crystal; mp 76-79 °C; yield, 58%; [R]D20
)
+15.1 (c 1.8, acetone); IR (KBr, cm-1) ν 3298, 3133, 3064, 2968,
1
1541, 1494, 1452, 1352, 1213, 1012, 756, 698, 565, 549; H NMR
(DMSO-d6, 500 MHz) δ 8.36 (1H, s, NH), 8.17 (1H, d, J ) 7.4, NH),
7.33-7.30 (10H, m, ArH), 6.17 (1H, s, N-CH-P), 5.41 (1H, br s,
N-CH-Ar), 3.84-3.74 (4H, m, 2OCH2), 1.53 (3H, d, J ) 18.0 Hz,
O,O′-Diisopropyl phenyl[3-((S)-1-cyclohexylethyl)thioureido]meth-
ylphosphonate (8k): white crystal; mp 123-124 °C; yield, 63%; [R]D20
) +10.5 (c 0.18, acetone); IR (KBr, cm-1) ν 3313, 3122, 3064, 2978,