1004
R. M. Steele et al. / Tetrahedron: Asymmetry 17 (2006) 999–1006
2
D
2
13
(2H, m), 7.79 (1H, br s). C NMR (CDCl ): d = 16.2,
1
80–181.5 ꢁC; ½aꢁ ¼ ꢀ485:0 (c 1.0, CHCl ). R (Et N/tol-
3
f
3
3
uene 1/9) = 0.21. IR (Nujol): t = 2361, 1521, 1289, 1174,
16.3, 21.6, 22.1, 24.4, 24.9, 32.1, 32.6, 39.8, 40.2, 55.5,
56.2, 66.3, 67.0, 107.0, 107.2, 127.9, 128.2, 130.4, 130.8,
133.1, 136.3, 141.1, 141.2, 181.2, 181.3, 189.0, 189.1.
ꢀ
1
1
1
062, 959 cm
.
H NMR(CDCl ): d = 1.02–1.43 (5H,
3
m), 1.67–1.76 (1H, m), 1.78–1.95 (2H, m), 2.08 (3H, d,
J = 0.8 Hz), 2.28 (6H, s), 2.30–2.45 (1H, m), 3.66 (1H, br
s), 6.37 (1H, q, J = 0.8 Hz), 6.69 (1H, br s), 7.20 (1H, d,
J = 7.8 Hz), 7.45 (1H, dd, J = 7.2, 7.8 Hz), 7.57 (1H, dd,
J = 7.2, 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 8.30 (1H, br s).
+
HRMS (ESI) [M+H] , found 407.13915. C H N S
1
9
26
4
3
+
requires [M+H] , 407.13924.
4.9. 1-(2-Dimethylamino-cyclohexyl)-3-phenyl-thiourea 5
1
3
C NMR (CDCl ): d = 17.0, 22.9, 25.1, 25.7, 33.4, 40.9,
3
5
1
4
6.9, 67.7, 107.7, 128.6, 128.9, 130.9, 131.1, 133.8, 137.0,
A mixture of phenyl isothiocyanate (88 lL, 0.74 mmol) and
(R,R)-N,N-dimethyl-1,2-diaminocyclohexane 4 (105 mg,
0.74 mmol) in dry benzene was stirred at room tempera-
ture, under argon, for 4 h. The solvent was removed under
reduced pressure. Purification by column chromatography,
eluting with CHCl /MeOH/Et N 100:5:1, gave 5 as a pale
+
41.6, 182.0, 189.8. HRMS (ESI) [M+H] , found
+
07.13857. C H N S requires [M+H] , 407.13924.
1
9
26
4 3
4.7. (aR)-1-((1S,2S)-2-Dimethylamino-cyclohexyl)-3-[2-(4-
methyl-2-thioxo-thiazol-3-yl)-phenyl]-thiourea (aR)-(S,S)-1
3
3
2
5
yellow gum (190 mg, 92%); ½aꢁ ¼ ꢀ115:2 (c 1.0, CHCl )
D
3
4
c
21
D
1
To a solution of the (aR)-3-(2-isothiocyanato-phenyl)-4-
methyl-thiazoline-2-thione 3 (85 mg, 0.321 mmol) in dry
acetonitrile (2.0 mL), under argon, a solution of (S,S)-
N,N-dimethyl-1,2-diaminocyclohexane 4 (54 mg, 0.385
mmol) was added in acetonitrile (0.3 mL). The reaction
mixture was stirred at room temperature for 17 h. The sol-
vent was removed under reduced pressure and the crude
purified by column chromatography, eluting with 5–10%
triethylamine/toluene, giving (aR)-(S,S)-1 as an off-white
amorphous solid (74 mg, 57%), mp (decomp.) 80–83 ꢁC;
{lit. ½aꢁ ¼ ꢀ112 (c 0.98, CHCl )}. H NMR (CDCl ):
3
3
d = 0.96–1.10 (1H, m), 1.11–1.28 (2H, m), 1.28–1.40 (1H,
m), 1.67 (1H, br d, J = 14.4 Hz), 1.75–1.90 (2H, m), 2.21
(6H, s), 2.38 (1H, td, J = 3.2, 10.8 Hz), 2.66 (1H, m),
3.95 (1H, br s), 7.08 (1H, br s), 7.14–7.22 (1H, m), 7.28–
1
3
7.37 (4H, m), 8.80 (1H, br s). C NMR (CDCl3):
d = 22.1, 25.1, 25.7, 33.4, 40.4, 56.7, 67.3, 125.1, 126.6,
130.0, 138.1, 180.3.
4.10. General procedure for the organocatalysed cyanosilyl-
ation of aldehydes 6
2
D
2
½
aꢁ ¼ ꢀ358:2 (c 1.0, CHCl ); R (Et N/toluene 1/9) =
3
f
3
0
9
1
.21. IR (Nujol): t = 2361, 1521, 1289, 1174, 1062,
ꢀ
1 1
59 cm
.
H NMR(CDCl ): d = 1.00–1.45 (5H, m),
A mixture of freshly distilled aldehyde (0.20 mmol) and the
thiourea catalyst (8 mg, 0.02 mmol) in dry CH Cl
3
.63–1.78 (1H, m), 1.79–1.91 (2H, m), 2.07 (3H, d,
2
2
J = 0.8 Hz), 2.16 (6H, s), 2.45–2.57 (1H, m), 3.47–3.68
(500 lL), under argon, was cooled to ꢀ20 ꢁC. Tri-
methylsilylcyanide (80 lL, 0.60 mmol) was added and the
mixture stirred at ꢀ20 ꢁC for 24 h. The reaction was
quenched by addition of water (400 lL), then the organic
layer separated and purified by column chromatography,
eluting with 5% EtOAc/hexane to give the isolated yield
of the corresponding cyanohydrin trimethylsilylether 7.
(
(
1H, m), 6.37 (1H, q, J = 0.8 Hz), 6.80 (1H, br s), 7.21
1H, dd, J = 1.4, 7.6 Hz), 7.45 (1H, td, J = 1.4, 7.6 Hz),
7
7
2
1
.57 (1H, td, J = 1.4, 7.6 Hz), 7.72 (1H, dd, J = 1.4,
1
3
.6 Hz), 7.90 (1H, br s). C NMR (CDCl ): d = 16.2,
3
1.5, 24.5, 24.6, 25.0, 39.8, 55.7, 66.2, 107.1, 128.1, 128.3,
30.5, 130.8, 133.3, 136.2, 141.3, 181.2, 189.1. HRMS
+
(
ESI) [M+H] , found 407.13945. C H N S requires
1
9
26
4 3
+
[
M+H] , 407.13924.
4.11. Derivatisation of cyanohydrin trimethylsilylethers 7
4
.8. (aR/aS)-1-((1R,2R)-2-Dimethylamino-cyclohexyl)-3-[2-
The cyanohydrin trimethylsilylether 7 in CH Cl was trea-
2
2
(
(
4-methyl-2-thioxo-thiazol-3-yl)-phenyl]-thiourea (aR/aS)-
R,R)-1
ted with 2 M aqueous HCl, at room temperature, for 2 h.
The organic layer was separated and dried (Na SO ), then
2
4
treated with acetic anhydride (160 lL) and pyridine (40 lL)
for 5 h at room temperature. The reaction mixture was
concentrated under reduced pressure and the residue puri-
fied by column chromatography, eluting with 5% EtOAc/
hexane, giving the corresponding acetate 8. The enantio-
meric purity of the acetate was determined by GC analysis.
Conditions: DMePentilBETACDX (OV1701) column
(25 m length · 0.25 mm ID · 0.25 lm film thickness); car-
To a solution of the (aR/aS)-3-(2-isothiocyanato-phenyl)-
-methyl-thiazoline-2-thione 3 (200 mg, 0.756 mmol) in
dry acetonitrile (4.0 mL), under argon, a solution of
R,R)-N,N-dimethyl-1,2-diaminocyclohexane 4 (128 mg,
.906 mmol) was added in acetonitrile (0.6 mL). The reac-
tion mixture was stirred at room temperature for 18 h. A
colourless solid was precipitated out from the reaction
mixture and collected by filtration and dried, giving
4
(
0
rier H (100 kPa); inject temperature = 225 ꢁC; detector
2
(
1
aR/aS)-(R,R)-1 as a colourless solid (205 mg, 67%), mp
temperature = 225 ꢁC.
22
77.5–179.5 ꢁC; ½aꢁ ¼ ꢀ18:5 (c 1.0, CHCl ); R (Et N/
D
3
f
3
toluene 1/9) = 0.21. IR (Nujol): t = 2361, 1521, 1289,
1
4.12. (S)-(ꢀ)-2-Acetyloxy-2-phenylacetonitrile 8a
ꢀ1
1
174, 1062, 959 cm . H NMR(CDCl ): d = 1.02–1.43
3
25
23
24
D
(
(
10H, m), 1.67–1.76 (2H, m), 1.78–1.92 (4H, m), 2.08
3H, d, J = 1.2 Hz), 2.09 (3H, d, J = 1.2 Hz), 2.23 (6H,
½aꢁ ¼ ꢀ7:0 (c 0.60, CHCl ) for 66.3% ee {lit. ½aꢁ
¼
D
3
1
ꢀ7:24 (c 2.3, CHCl ) for >99.0% ee (S)}. H NMR
3
s), 2.27 (6H, s), 2.30–2.42 (1H, m), 2.43–2.55 (1H, m),
.66 (2H, br s), 6.37 (1H, q, J = 1.2 Hz), 6.38 (1H, q,
J = 1.2 Hz), 6.70 (1H, br s), 7.00 (2H, br s), 7.18–7.23
2H, m), 7.42–7.48 (2H, m), 7.54–7.61 (2H, m), 7.75–7.79
(CDCl ): d = 2.19 (3H, s), 6.44, (1H, s), 7.48 (3H,
3
1
3
3
m), 7.55 (2H, m). C NMR (CDCl ): d = 21.1, 63.5,
3
116.7, 128.5, 129.9, 131.0, 132.4, 169.5. Enantiomeric
excess determined by chiral GC: 66.3% ee; tR1 = 5.690 min
(