(qd, J = 14.0, 7.2 Hz, 2H), 3.33 (dt, J = 8.4, 5.6 Hz, 1H), 1.97–
1.55 (m, 6H), 1.40–1.08 (m, 5H). 13C NMR (75 MHz, CDCl3) d
117.3, 73.2, 37.4, 36.0, 30.9, 29.0, 25.6, 25.4, 25.3. Anal. Calcd. for
C9H14N2O2: C 59.32%, H 7.74%, N 15.37%. Found C 58.93%, H
6.99%, N 14.89%.
General procedure for the asymmetric cyanation of nitroolefins at
room temperature
After stirring a solution of freshly distilled Ti(OiPr)4 (5.8 mL,
0.02 mmol, 20 mol%) and L2* (10.9 mg, 0.02 mmol, 20 mol%)
in toluene (2 mL) under Ar for 15 min at room temperature,
nitroolefin 1 (0.1 mmol) was added. TMSCN (20.0 mL, 0.15 mmol,
150 mol%) was added to the reaction mixture in one-pot. When
the reaction was completed (monitored by TLC), the product was
obtained following a general work-up procedure.
(S)-2-(Nitromethyl)hexanenitrile (3c). 90% yield, 91 : 9 e.r. was
determined by HPLC analysis (OD-H column, hexane/iPrOH =
95/5); retention times: tmajor = 23.8, tminor = 27.3. [a]2D1 -19.8 (c 1.01,
CHCl3). 1H NMR (300 MHz, CDCl3) d 4.57 (ddd, J = 20.2, 13.9,
7.0 Hz, 2H), 3.40 (ddd, J = 16.5, 7.8, 6.2 Hz, 1H).1.80–1.65 (m,
2H), 1.65–1.47 (m, 2H), 1.46–1.32 (m, 2H), 0.95 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 118.0, 74.6, 29.8, 29.1, 28.6,
21.9, 13.6. Anal. Calcd. for C7H12N2O2: C 53.83%, H 7.74%, N
17.94%. Found C 54.00%, H 7.67%, N 16.62%.
(S)-2-(((tert-Butoxycarbonyl)amino)methyl)-3-methylbutanoic
acid 8. To a stirred solution of 3a (142 mg, 1 mmol) in EtOH
(10 mL) was added zinc powder (0.98 g, 15 equ.) and 5 mL of
6 M HCl (aq.). The reaction was stirred for 1h. Excess zinc
powder was removed by filtration, the EtOH was removed in
vacuo. NaOH (15%) was added to the above mixture until pH
10. The aqueous layer was extracted with CH2Cl2 (3 ¥ 10 mL),
the combined organic layer was washed with brine, dried, and
concentrated to give the crude amine 6, which was used for the
next step without purification.
To the above residue was added 5 mL H2SO4 (75%) and heated
at reflux for 2 h. The solution was then cooled to 0 ◦C and carefully
adjusted to pH 10 with 40% NaOH. Dioxane (5 mL) was added
to the above aqueous solution followed by (Boc)2O (240 mg, 1.1
eq. according to the starting loading of 3a). The solution was
warmed to room temperature and stirred for 1 h. The dioxane was
removed in vacuo, the aqueous layer was acidified to pH 2 with
1 M NaHSO4 and extracted with ethyl acetate (2 ¥ 15 mL). The
organic phase was dried and concentrated in vacuo. The residue
was purified by flash column chromatography on SiO2 (33% ethyl
acetate/hexane) to afford 8 as a white solid (81.3 mg, 35.2% from
3a). [a]rDt +3◦ (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d 10.6
(br,1H), 6.70 & 5.03 (br, 1H), 3.44–3.40 (m, 1H), 3.28–3.09 (m,
1H), 2.52–2.38 (m, 1H), 2.05–1.90 (m, 1H), 1.48–1.44 (m, 9H),
1.02–0.96 (m, 6H). 13C NMR (75 MHz, CDCl3): d 179.8 & 178.3,
158.1 & 155.9, 81.0&79.6, 52.8 & 52.1, 40.7&39.5, 28.7, 28.3, 28.2,
20.4, 20.3, 19.8. ESI-MS (M+H)+: 232.1.15
3,3-Dimethoxy-2-(nitromethyl)propanenitrile (3d). 74% yield,
86 : 14 e.r. was determined by HPLC analysis (AD-H column,
hexane/iPrOH = 97/3); retention times: tminor = 36.3, tmajor = 38.9.
1
[a]2D1 +2.9 (c 0.68, CHCl3). H NMR (300 MHz, CDCl3) d 4.77–
4.61 (m, 3H), 3.70–3.62 (m, 1H), 3.51 (d, J = 1.3 Hz, 6H). 13C NMR
(75 MHz, CDCl3) d 115.7, 101.8, 70.8, 56.7, 56.3, 34.5. Anal.
Calcd. for C6H10N2O4: C 41.38%, H 5.79%, N 14.35%. Found C
43.83%, H 6.12%, N 14.24%.
4 - ((tert - Butyldimethylsilyl)oxy) - 2 - (nitromethyl)butanenitrile
(3e). 83% yield, 80 : 20 e.r. was determined by HPLC analysis
(OD-H column, hexane/iPrOH = 95/5); retention times: tmajor
=
14.0, tminor = 15.9. [a]D21 -13.1 (c 0.61, CHCl3). 1H NMR (300 MHz,
CDCl3) d 4.79–4.57 (m, 2H), 3.91–3.77 (m, 2H), 3.73–3.61 (m, 1H),
0.91 (s, 9H), 0.09 (s, 6H). 13C NMR (75 MHz, CDCl3) d 117.9,
74.5, 59.2, 32.1, 27.1, 25.8, 18.1, -5.6. HRMS (ESI): C11H22N2O3Si
+NH4, Calc: 276.1738, Found: 276.1733.
5-((Tert-butyldimethylsilyl)oxy)-2-(nitromethyl)pentanenitrile
(3f). 44% yield, 85 : 15 e.r. was determined by HPLC analysis (OJ
column, hexane/iPrOH = 98/2); retention times: tminor = 17.4, tmajor
= 19.5. [a]2D1 -9.7 (c 0.72, CHCl3). 1H NMR (300 MHz, CDCl3) d
4.64 (dd, J = 14.0, 7.8 Hz, 1H), 4.52 (dd, J = 14.0, 6.1 Hz, 1H),
3.75–3.63 (m, 2H), 3.61–3.47 (m, 1H), 1.88–1.67 (m, 4H), 0.89 (s,
9H), 0.06 (s, 6H). 13C NMR (75 MHz, CDCl3) d 118.0, 74.7, 61.8,
29.6, 29.3, 26.6, 25.8, 18.2, -5.5. HRMS (ESI): C12H24N2O3Si +H,
Calc: 273.1629, Found: 273.1631.
Procedure for the in situ 1H NMR investigation
To an NMR tube was added L2* (5.5 mg, 0.01 mmol, 20 mol%),
Ti(OiPr)4 (2.9 mL, 0.01 mmol, 20 mol%), and 1a (0.05 mmol) in 1
mL CDCl3. 1H NMR S1 was obtained after the reaction mixture
had been left for 15 min at room temperature. After addition of
150 mol% of TMSCN to the above mixture, S2, S3 and S4 were
obtained after standing for 2 min, 5 min and 20 min, respectively.
S5 was obtained after quenching the reaction with 0.5 mL H2O.
2-Nitrocyclohexanecarbonitrile (anti-3g)8. 60% yield, 74 : 26
e.r. was determined by HPLC analysis (OJ column, hexane/iPrOH
= 85/15); retention times: tmajor = 27.0, tminor = 32.1. [a]2D8 +28.2
(c 0.78, CHCl3). 1H NMR (300 MHz, CDCl3) d 4.55 (td, J = 10.3,
4.2 Hz, 1H), 3.23 (ddd, J = 11.1, 9.9, 4.1 Hz, 1H), 2.53–2.35 (m,
1H), 2.33–2.19 (m, 1H), 1.95–1.77 (m, 3H), 1.76–1.62 (m, 1H),
1.54–1.30 (m, 2H). 13C NMR (75 MHz, CDCl3) d 118.4, 84.6,
31.8, 30.5, 27.9, 23.2, 23.1.
Acknowledgements
We gratefully acknowledge financial support from NSFC (nos.
21002043, 20932003, and 90813012) and the National S&T Major
Project of China (2009ZX09503-017).
2-Nitrocyclohexanecarbonitrile (syn-3g)8. 60% yield, 73 : 27 e.r.
was determined by HPLC analysis (AD-Hcolumn, hexane/iPrOH
= 95/5); retention times: tmajor = 21.7, tminor = 23.3. [a]2D8 +37.5
(c 0.64, CHCl3). 1H NMR (300 MHz, CDCl3) d 4.36 (dt, J = 11.7,
4.0 Hz, 1H), 3.76–3.63 (m, 1H), 2.44 (m, 1H), 2.32–2.17 (m, 1H),
2.17–2.09 (m, 1H), 2.01 (m, 1H), 1.80–1.61 (m, 3H), 1.51–1.32 (m,
1H). 13C NMR (75 MHz, CDCl3) d 117.3, 82.4, 32.0, 28.1, 26.9,
23.6, 20.9.
Notes and references
1 Selected reviews: (a) D. Seebach and J. L. Matthews, Chem. Commun.,
1997, 2015; (b) D. Seebach and J. Gardiner, Acc. Chem. Res., 2008, 41,
1366.
88 | Org. Biomol. Chem., 2012, 10, 83–89
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