6
A.M. Fields, S. Jones / Tetrahedron xxx (xxxx) xxx
(ESIþ) 357 (5%), 335.2165 (20, M þ Hþ.C18H31N2O2Si requires
335.2149), 188 (70), 121 (100): major isomer 17 (assumed to be syn)
M þ Hþ.C18H31N2OSi requires 319.2200), 292 (3), 215 (1), 188 (50).
Diastereoisomer 21; ½aꢃ2D3 þ36.5 (c 1.00 in CHCl3); nmax/cmꢀ1 (film)
3329, 2956, 2930, 2886, 2857, 2232, 1493, 1471; dH (400 MHz;
CDCl3) 7.39e7.30 (5H, m, ArCH), 4.13e4.01 (2H, m, CHN and CHO),
3.13 (1H, d, J 3.6, CHCN), 1.44 (3H, d, J 6.5, CH3), 1.28 (3H, d, J 6.2,
CH3), 0.92 [9H, s, (CH3)3C], 0.11 (3H, s, CH3Si), 0.09 (3H, s, CH3Si); dC
(100 MHz; CDCl3) 143.5 (ArC), 128.7 (2 ꢂ ArCH), 127.6 (ArCH), 126.8
(2 ꢂ ArCH), 119.6 (CN), 68.8 (CH), 56.1 (CH), 54.9 (CH), 25.8
[(CH3)3CSi], 25.1 (CH3) 20.0 (CH3), 18.0 [(CH3)3CSi], ꢀ4.5
(CH3Si), ꢀ5.0 (CH3Si); m/z (ESIþ) 319.2230 (100%, M þ Hþ.
½aꢃD21 þ135.0 (c 2.80 in CHCl3); vmax (cmꢀ1) 2932, 2955, 2857, 2228,
1682, 1613, 1514; dH (400 MHz; CDCl3) 7.33e7.28 (2H, m, ArH), 6.92
(2H, m, ArH), 4.11e4.05 (2H, m, CHH and CH), 3.85 (1H, m, CHH),
3.82 (3H, s, CH3), 3.40 (1H, d, J 3.0, CH), 1.32 (3H, d, J 6.2, CH3), 0.92
[9H, s, (CH3)3C], 0.13 (3H, s, CH3Si), 0.12 (3H, s, CH3Si); dC (100 MHz;
CDCl3) 161.3 (ArC), 139.4 (ArC), 129.8 (2 ꢂ ArCH), 122.9 (CN), 114.0
(2 ꢂ ArCH), 68.8 (CH), 56.8 (CH3), 55.3 (CH), 50.8 (CH2), 25.7
[(CH3)3C], 21.0 (CH3), 17.2 [(CH3)3C], ꢀ4.3 (CH3Si), ꢀ4.7 (CH3Si); m/z
(ESIþ) 357 (5%), 335.2158 (17, M þ Hþ.C18H31N2O2Si requires
335.2149), 188 (69), 121 (100).
C18H31N2OSi requires 319.2225), 188 (36).
4.13. (2R,3S) and (2S,3S)-3-[(t-butyldimethylsilyl)oxy]-2-{[(1S)-1-
phenylethyl]amino}butanenitrile 22 & 23
4.11. (2R, 3S) and (2S, 3S)-3-(t-butyldimethylsilyloxy)-2-N-[(p-
methoxyphenyl)amino]butanenitrile 18 & 19
TMSCN (0.26 mL, 2.06 mmol) was added to a solution of the
imine 11 (0.50 g,1.71 mmol) in DCM (3 mL) followed by ZnI2 (0.05 g,
0.17 mmol). The reaction mixture was stirred at room temperature
for 24 h, then quenched with NH4Cl(aq) (10 mL) and extracted with
DCM (3 ꢂ 5 mL). The combined organic extracts were dried with
MgSO4, filtered, and concentrated under reduced pressure to give
the crude a-aminonitrile (0.51 g) as a mixture of diastereoisomers
(syn: anti 10:90) which was purified by flash column chromatog-
raphy on silica gel eluting with toluene to give the individual di-
MgSO4 (1.00 g) was added in a single portion to a solution of the
aldehyde 5 (0.29 g, 1.56 mmol) in DCM (2.5 mL). p-Methoxyphenyl
amine (0.19 g, 1.50 mmol) was added and the mixture was stirred at
room temperature for 16 h before being filtered and concentrated
to give the crude imine which was immediately dissolved in DCM
(2.5 mL). ZnI2 (0.05 g, 0.16 mmol) was added, followed by TMSCN
(2.3 mL, 1.87 mmol), and the mixture was left to stir for 24 h. The
reaction mixture was quenched with NH4Cl(aq) (1.0 mL), extracted
with DCM (4 ꢂ 2.0 mL), dried with MgSO4, filtered, and concen-
astereoisomers 22 & 23 as clear oils: major isomer anti-22; ½aꢃD23
-9.2 (c 1.00 in CHCl3); nmax/cmꢀ1 (film) 2963, 2932, 2860, 2163,
1452, 1254, 835; dH (400 MHz; CDCl3) 7.41e7.21 (5H, m, ArCH), 4.11
(1H, q, J 6.5, CHN), 3.80 (1H, qd, J 6.2, 3.8, CHO), 3.07 (1H, br s,
CHCN), 1.85 (1H, br d, J 5.2, NH), 1.40 (3H, d, J 6.5, CH3), 1.26 (3H, d, J
6.3, CH3), 0.93 [9H, s, (CH3)3C], 0.18 (3H, d, CH3Si), 0.14 (3H, s,
CH3Si); dC (100 MHz; CDCl3) 143.6 (ArC), 128.7 (2 ꢂ ArCH), 127.6
(ArCH), 126.7 (2 ꢂ ArCH), 118.5 (CN), 69.1 (CH), 56.1 (CH), 56.0 (CH),
25.8 [(CH3)3C], 25.0 (CH3), 21.0 (CH3), 18.0 [(CH3)3 CSi], ꢀ4.3
(CH3Si), ꢀ4.8 (CH3Si); m/z (ESIþ) 319.2202 (100%, M þ Hþ.
trated to give the crude major and minor diastereoisomers of the a-
aminonitrile as a pink oil (0.38 g,1.17 mmol, 75%, 45 : 55) which was
purified by column chromatography on silica using petroleum
ether 40/60 and ethyl acetate (19:1) to give an analytically pure
mixture of diastereoisomers 18 & 19 as a clear oil: ½aꢃ2D2 þ46.1 (c 3.40
in CHCl3); vmax/cmꢀ1 (film) 2957, 2930, 2858, 2229, 1493, 1471,
1452; dH (400 MHz; CDCl3) 6.88e6.84 (2H, m, ArCH), 6.75e6.70
(2H, m, ArCH), 4.33 (1H, qd, J 6.2, 2.8, CH major), 4.18 (1H, qd, J 6.2,
3.6, CH minor), 3.97e3.91 (1H, m, NH), 3.79 (3H, s, CH3), 1.43 (3H, d, J
6.2, CH3 minor), 1.38 (3H, d, J 6.2, CH3 major), 0.98 [9H, s, C(CH3)3 minor],
0.97 [9H, s, C(CH3)3 major], 0.21 [3H, s, (CH3)2Si major], 0.19 [3H, s,
(CH3)2Si minor], 0.18 [3H, s, (CH3)2Si]; dC (100 MHz; CDCl3) 153.9
(ArC), 139.0 (ArC), 119.1 (CN major), 118.7 (CN minor), 116.4 (ArCH),
116.1 (2 ꢂ ArCH), 115.0 (2 ꢂ ArCH), 68.8 (CH major), 68.6 (CH minor),
55.7 (CH3), 54.7 (CH minor), 53.5 (CH major), 25.8 [(CH3)3C], 21.0 (CH3
minor), 20.5 (CH3 major), 18.0 [(CH3)3C], ꢀ4.4 (CH3Si), ꢀ4.9 (CH3Si); m/
z (ESIþ) 321.1996 (100% M þ Hþ.C17H29N2O2Si requires 321.1993).
C18H31N2OSi requires 319.2225), 188 (35): minor isomer syn-23;
½aꢃD23 -18.0 (c 1.0 in CHCl3); nmax/cmꢀ1 (film) 2959, 2932, 2860, 2160,
1467, 1467, 1254, 839; dH (400 MHz; CDCl3) 7.42e7.28 (5H, m,
ArCH), 4.14 (1H, qd, J 6.2, 3.9, CHO), 4.05 (1H, q, J 6.4, CH3CH), 3.60
(1H, d, J 3.9, CHCN), 1.82 (1H, br s, NH), 1.37 (3H, d, J 6.4, CH3CHN),
1.34 (3H, d, J 6.2, CH3CHO), 0.91 [9H, s, (CH3)3C], 0.14 (3H, s, SiCH3),
0.12 (3H, s, SiCH3); dC (100 MHz; CDCl3) 144.6 (ArC), 128.7
(2 ꢂ ArCH), 127.6 (ArCH), 126.7 (2 ꢂ ArCH), 119.2 (CN), 68.9 (CH),
56.2 (CH), 55.1 (CH), 25.7 [(CH3)3C], 22.1 (CH3), 20.0 (CH3), 18.0
[(CH3)3C], ꢀ4.5 (CH3Si), ꢀ4.9 (CH3Si); m/z (ESIþ) 319.2196 (100%,
M þ Hþ. C18H31N2OSi requires 319.2200), 188 (45).
4.12. (2R,3S) and (2S,3S)-3-[(t-butyldimethylsilyl)oxy]-2-{[(1R)-1-
phenylethyl]amino}butanenitrile 20 & 21
TMSCN (0.26 mL, 2.06 mmol) was added to a solution of imine
10 (0.50 g, 1.71 mmol) in DCM (3 mL) followed by ZnI2 (0.05 g,
0.17 mmol). The reaction mixture was stirred at room temperature
for 24 h, then quenched with NH4Cl(aq) (10 mL) and extracted with
DCM (3 ꢂ 5 mL). The combined organic extracts were dried with
MgSO4, filtered, and concentrated under reduced pressure to give
the crude a-aminonitrile (0.53 g) as a mixture of diastereoisomers
(syn: anti 78:29) which was purified by flash column chromatog-
raphy on silica gel eluting with toluene to give the individual di-
4.14. (2S,3S)-3-hydroxy-2-{[(1R)-1-phenylethyl]amino}-
butanenitrile 24
A solution of the silyl ether 21 (0.80 g, 2.50 mmol) in THF was
cooled to 0 ꢁC and TBAF (1 M in THF, 2.5 mL, 2.5 mmol) was added
dropwise. The reaction mixture was stirred for 3 h before being
concentrated, and adding DCM (5 mL) and H2O (10 mL). The organic
layer was separated and the aqueous layer extracted with DCM
(3 ꢂ 5 mL). The combined organic extracts were washed with
K2CO3(aq) (10 mL), dried with MgSO4, filtered, and concentrated
under reduced pressure to give a yellow oil. This was purified by
flash column chromatography on silica gel eluting with petroleum
ether 40/60 and ethyl acetate (4:1) to give the alcohol 24 (0.43 g,
83%) as a colourless oil; ½aꢃ2D3 þ29.0 (c 0.30 in CHCl3); nmax/cmꢀ1
(film) 3428, 3325, 3029, 2976, 2929, 2231, 1493, 1452; dH (400 MHz;
CDCl3) 7.39e7.28 (5H, m, ArCH), 4.13 (1H, q, J 6.5, CH), 3.89 (1H,
quin, J 6.4, CH), 3.04 (1H, d, J 7.0, CH), 2.96 (1H, br s, NH), 1.74 (1H, br
s, OH), 1.45 (3H, d, J 6.5, CH3), 1.31 (3H, d, J 6.4, CH3); dC (100 MHz;
astereoisomers 20
& 21 as clear oils. Diastereoisomer 20;
½aꢃD22 þ56.2 (c 1.00 in CHCl3); nmax/cmꢀ1 (film) 3057, 2987, 2305,
1760, 1398; dH (400 MHz; CDCl3) 7.40e7.21 (5H, m, ArCH),
4.12e3.98 (2H, m, CHN and CHO), 3.52 (d, 1H, J 3.8 Hz, CHCN), 1.37
(3H, d, J 6.5, CH3),1.34 (d, J 6.2, CH3), 0.87 [9H, s, (CH3)3C], 0.12 (s, 3H,
CH3Si), 0.10 (s, 3H, CH3Si); dC (100 MHz; CDCl3) 144.6 (ArC), 128.6
(2 ꢂ ArCH), 127.5 (ArCH), 126.6 (2 ꢂ ArCH), 118.2 (CN), 68.6 (CH),
55.9 (CH), 55.8 (CH), 25.8 [(CH3)3CSi], 22.4 (CH3), 21.1 (CH3), 18.0
[(CH3)3CSi], ꢀ4.3 (CH3Si), ꢀ4.9 (CH3Si); m/z (ESIþ) 319.2196 (100%,
Please cite this article as: A.M. Fields, S. Jones, Synergistic substrate and catalyst effects in the addition of trimethylsilyl cyanide to imines