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DOI: 10.1055/s-2008-1078496
Organocatalyzed Enantioselective Synthesis of Nitroalkanes Bearing All-Carbon Quaternary Stereogenic Centers through Conjugate Addition of Acetone Cyanohydrin
Publication History
Publication Date:
11 June 2008 (online)
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Abstract
The first organocatalyzed phase-transfer enantioselective conjugate addition of cyanide ion derived from acetone cyanohydrin to β,β′-disubstituted nitroolefins is reported. The reaction leads to the efficient formation of nitroalkanes bearing an all-carbon quaternary stereogenic center in up to 72% ee.
Key words
asymmetric synthesis - conjugate addition - cyanohydrins - organocatalysis - quaternary stereogenic center
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References and Notes
N , O -Di[3,5-bis(trifluoromethyl)benzyl]cinchoninium bromide (2c): 3,5-Bis(trifluoromethyl)benzyl bromide (0.48 mL, 2.6 mmol) was added to a suspension of cinchonine (0.59 g, 2.0 mmol) in toluene (6 mL). The mixture was vigorously stirred at 90 ˚C for 18 h and then cooled to r.t. and filtered. The white solid obtained (0.82 g, 68%) was washed with toluene (2 × 25 mL), dried under reduced pressure and used without further purification. 3,5-Bis(trifluoromethyl)benzyl bromide (0.37 mL, 2.0 mmol) and 50% aq NaOH (53 mg, 1.33 mmol) were added to a solution of N-3,5-bis(trifluoromethyl)benzylcinchoninium bromide (0.4 g, 0.66 mmol) in CH2Cl2 (7 mL). The reaction mixture was stirred for 6 h at r.t. and then quenched by addition of H2O. The aqueous layer was extracted with CH2Cl2 (2 × 5 mL) and the combined organic layers were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel column with hexane-EtOAc-MeOH-CH2Cl2 (5:4:2:1) as eluent to give the title product as a pale yellow solid (0.32 g, 58%); mp 162-165 ˚C; [α]D ²0 +48.3 (c = 0.94, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 8.93 (br s, 1 H), 8.74 (d, J = 7.4 Hz, 1 H), 8.37 (s, 2 H), 8.06 (s, 2 H), 7.90 (s, 2 H), 7.81 (s, 1 H), 7.54 (t, J = 7.05 Hz, 2 H), 7.43 (m, 1 H), 6.76 (br s, 1 H), 6.60 (d, J = 12.3 Hz, 1 H), 5.80 (m, 1 H), 5.53 (d, J = 12.4 Hz, 1 H), 5.23 (d, J = 10.5 Hz, 2 H), 5.04 (d, J = 17.0 Hz, 2 H), 4.82 (d, J = 12.4 Hz, 1 H), 4.65 (br s, 1 H), 4.15 (t, J = 10.0 Hz, 1 H), 3.29 (t, J = 11.0 Hz, 1 H), 2.65 (m, 1 H), 2.49 (m, 3 H), 1.84 (m, 2 H), 1.49 (m, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 149.2, 148.5, 139.4, 139.3, 139.0, 134.5, 134.05, 132.4 (q, J = 34 Hz), 130.0, 129.9, 128.8, 127.8, 127.5, 123.05 (q, J = 273 Hz, CF3), 124.9, 124.4, 122.5 (q, J = 273 Hz, CF3), 122.4, 118.4, 75.1, 69.9, 66.8, 60.9, 56.0, 55.0, 37.3, 26.8, 23.4, 22.1. ¹9F NMR (376 MHz, CDCl3): δ = 62.9 (s, 6 F), -63.0 (s, 6 F). IR (CHCl3): 3367, 3030, 2960, 1371, 1278, 1176, 1142, 903 cm-¹. ESI-MS (+): m/z = 779 [M+]. ESI-MS (-): m/z = 81, 79 [M-]. Anal. Calcd for C37H31BrF12N2O: C, 53.70; H, 3.78; N, 3.39. Found: C, 53.74; H, 3.72; N, 3.44.
20
General Procedure
for the Hydrocyanation of β,β′-Disubstituted
Nitroolefins: Catalyst (8.3 mg, 0.01 mmol) was added to a screw-tapped
test tube that contained a mixture of nitroolefin (0.1 mmol), acetone
cyanohydrin (0.018 mL, 0.2 mmol) and toluene (1 mL). After the resulting
mixture had been cooled to -30 ˚C finely powdered K2CO3 (28
mg, 0.2 mmol) was added in one portion. The reaction mixture was
then vigorously stirred at the same temperature without any precaution
to exclude moisture or air. After 72 h, the reaction product was
directly isolated by column chromatography on silica gel with hexane-EtOAc (5:1)
as eluent.
2-Methyl-3-nitro-2-phenylpropanenitrile:
HPLC on an AD-H column with hexane-i-PrOH
(80:20) as eluent, flow rate: 0.75 mL min-¹, t
R = 9.37 min (major), t
R = 10.40 min (minor), λ = 220
nm; [α]D
²0 +12.4
(c = 0.45, CHCl3). ¹H NMR
(400 MHz, CDCl3): δ = 7.38-7.53
(m, 5 H), 4.78 (d, J = 13.0
Hz, 1 H), 4.72 (d, J = 13.0
Hz, 1 H), 1.90 (s, 3 H). ¹³C NMR (150
MHz, CDCl3): δ = 135.0, 129.6, 129.3, 125.5,
119.95, 81.6, 41.3, 24.8. IR (CHCl3): 3021, 2928, 2855,
2248, 1562, 1449, 1374, 780, 700 cm-¹.
ESI-MS
(+): m/z = 213 [M+ + Na].
2-Methyl-2-(naphthalen-2-yl)-3-nitropropanenitrile: HPLC
on an AD-H column with hexane-i-PrOH
(95:5) as eluent, flow rate: 0.50 mL min-¹, t
R = 52.59 min (minor),
t
R = 54.75 min (major), λ = 254
nm; [α]D
²0 +11.6
(c = 0.59, CHCl3);
mp 133-135 ˚C. ¹H NMR (400
MHz, CDCl3): δ = 8.03 (d, J = 2.2 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.87 (m, 2
H), 7.57 (m, 2 H), 7.51 (dd, J
1 = 8.7
Hz, J
2 = 2.2 Hz,
1 H), 4.89 (d, J = 13.0 Hz,
1 H), 4.81 (d, J = 13.0 Hz,
1 H), 1.99 (s, 3 H). ¹³C NMR (150 MHz,
CDCl3): δ = 133.13, 133.07, 132.1,
129.75, 128.3, 127.7, 127.4, 127.3, 125.6, 122.0, 120.0, 81.45,
41.5, 24.8. IR (CHCl3): 3036, 2927, 2248, 1563, 1373
cm-¹. ESI-MS (+): m/z = 263 [M+ + Na].
2-(4-Chlorophenyl)-2-methyl-3-nitropropanenitrile: HPLC
on an AD-H column with hexane-i-PrOH
(80:20) as eluent, flow rate: 0.75 mL min-¹, t
R = 10.63 min (minor), t
R = 11.85
min (major), λ = 220 nm; [α]D
²0 -16.7
(c = 0.65, CHCl3). ¹H
NMR (400 MHz, CDCl3): δ = 7.44 (s,
4 H), 4.74 (s, 2 H), 1.88 (s, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 135.4, 133.5,
129.7, 126.9, 119.5, 81.2, 40.9, 24.9. IR (CHCl3): 3054,
2927, 2248, 1564, 1495, 1374, 1103, 1014, 815 cm-¹.
ESI-MS (+): m/z = 247 [M+ + Na].