Cyclic Nitronates in C–C Coupling Reactions
cal TLC are specified in parentheses after the Rf values. Visualiza-
tion for analytical TLC: UV (254 nm) and treatment with 4-
MeOC6H4CHO (for 5, 8, 10 and 12–14) or ninhydrin (for 9 and
11).
after quenching of the reaction mixture. After column chromatog-
raphy, nitroso acetal 2a (73 mg, 71%) was obtained as a white crys-
talline. Adduct 5a was not detected in the NMR spectra.
Transformations of Isoxazolidines 5
Procedures for the Preparation of Isoxazolidines 5 (see Table 1): Pro-
Transformations of 5c: CF3CO2H (0.0044 mL, 0.1 equiv.) was
added to a solution of trans-5c (200 mg, 0.58 mmol) in methanol
(3.0 mL) at room temp. After 1.5 h at room temp., triethylamine
(0.016 mL, 0.2 equiv.) was added, and the resulting mixture was
concentrated in vacuo and the residue purified by gradient column
chromatography (ethyl acetate/hexane as eluent, from 1:3 to 1:1,
v/v). Isoxazolidine 8c (110 mg, 77% yield, colourless oil) was ob-
tained as an inseparable mixture of isomers (ca. 5:4 ratio), which
differ in the configuration of the nitrogen stereocentre. Isoxazolid-
ine 8c (154 mg, 0.62 mmol) was hydrogenated in the presence of
Raney nickel in methanol (3.0 mL, room temp., 40 bar, 24 h, stir-
ring). Then the catalyst was removed by filtration, washed with
methanol (2ϫ3.0 mL) and the combined filtrates were concen-
trated in vacuo. The residue was purified by gradient column
chromatography (ethyl acetate/methanol as eluent, from 1:0 to 10:1,
v/v) to give lactam 9a (66 mg, 56% yield) as a colourless viscous
oil.
cedure A is the General Procedure published in ref.[1]
Procedure B: The silyl ketene acetal 4 (1.1 equiv.) was added to a
solution of nitronate 3 (0.8–4.0 mmol, 1.0 equiv.) in CH2Cl2 (3 mL
per mmol of 3), and the solution was chilled to –94 °C (acetone/
liquid nitrogen). TBSOTf (0.2 equiv.) was added at –94 °C with stir-
ring, which was continued at –94 °C for the time indicated in
Table 1. Then the reaction mixture was quenched at –94 °C by the
successive addition of Et3N (0.3 equiv.) and methanol (0.25 equiv.).
After additional stirring at –94 °C for 2 min, hexane (6 mL per
mmol of 3) and water (3 mL per mmol of 3) were added, and the
reaction mixture was allowed to warm to room temperature. The
aqueous layer was separated and washed with hexane (2ϫ6 mL
per mmol of 3), and the combined organic layers were washed with
brine (one-third of the combined organic layers volume), dried with
anhydrous sodium sulfate and the solvents evaporated. Crude prod-
ucts were purified by gradient column chromatography with ethyl
acetate/hexane as eluent (from 1:30 to 1:10 by volume); unreacted
nitronate 3 (if remained) was eluted with pure ethyl acetate.
Alcoholysis of Isoxazolidines 5b,h: A solution of CF3CO2H in the
corresponding alcohol was added to a stirred solution of isoxazol-
idine in methanol or ethanol at room temp. in a quantity to obtain
a 0.001–0.006 solution of CF3CO2H. The reaction mixture was
stirred at room temp. for 1–6 h and then quenched with triethyl-
amine, concentated and purified by column chromatography or by
short-path distillation. For details of the reaction conditions and
characterization of the products, see the Supporting Information
Procedure C: The silyl ketene acetal 4 (1.1 equiv.) and 2,6-dimeth-
ylpyridine (0.25 equiv.) were added to a solution of nitronate 3
(0.8–5.0 mmol, 1.0 equiv.) in CH2Cl2 (3 mL per mmol of 3), and
the mixture was chilled to –78 °C (acetone/dry ice). TBSOTf
(0.2 equiv.) was added at –78 °C with stirring, which was continued
at –78 °C for the time indicated in Table 1. Then the mixture was
quenched at –78 °C by the addition of methanol (0.25 equiv.). After
additional stirring at –78 °C for 2 min, hexane (6 mL per mmol of
3) and water (3 mL per mmol of 3) were added, and the reaction
mixture was allowed to warm to room temperature. Further opera-
tions are the same as in Procedure B. For the exact amounts of
nitronates 3 and other reagents, as well as detailed characteriza-
tions of the isoxazolidines 5a–h, see the Supporting Information.
Transformations of Nitroso Compounds 10a,b
Hydrogenation of 10a in the Presence of Raney Nickel: The nitroso
compound 10a (105 mg, 0.45 mmol) was hydrogenated in the pres-
ence of Raney nickel in methanol (2.5 mL) and Boc2O (0.17 mL,
0.8 mmol) (room temp., 20 bar, 1 h, stirring). Then the catalyst was
removed by filtration, washed with methanol (2ϫ3.0 mL), and the
combined filtrates were concentrated in vacuo. Additional Boc2O
(0.2 mL) was added to the residue, and the resulting mixture was
kept at room temp. for 48 h. The residue was purified by gradient
column chromatography (ethyl acetate/hexane mixture as an eluent,
from 1:10 to 1:1, v/v) to give the protected amine 11 (87 mg, 61%
yield) as a colourless oil.
Competitive Reactions of Nitronates 1a and 3a with Silyl Ketene
Acetal 4
Experiment 1: TBSOTf (0.17 mL, 0.74 mmol) was added to a
stirred solution of nitronates 1a (51 mg, 0.23 mmol) and 3a (43 mg,
0.24 mmol), silyl ketene acetal 4 (45 mg, 0.24 mmol) and 2,6-di-
tert-butyl-4-methylpyridine (205 mg, 1.0 mmol) in CH2Cl2 (2.5 mL)
at –78 °C, and the reaction mixture was stirred at –78 °C for 1.5 h.
Then the reaction mixture was quenched at –78 °C by the success-
ive addition of Et3N (0.21 mL, 1.5 mmol) and MeOH (0.048 mL,
1.19 mmol). Further operations are the same as in procedure B
after quenching of the reaction mixture. After column chromatog-
raphy, an inseparable mixture (75 mg) of isoxazolidine 5a (yield
53% based on 3a, with a trans-5a/cis-5a ratio of ca. 3.0:1.0), nitroso
acetal 2a and dihydrooxazine 7 (in 4.4 and 36% yields, respectively,
based on 1a) was obtained as a colourless oil. Yields were derived
from the NMR molar ratio of the mixture of components and total
weight of the mixture.
Reduction of Nitroso Compounds 10a,b with Aluminium Amal-
gam:[22] Aluminium foil, cut into small pieces (0.8–1.0 mmol), was
added to a solution of the nitroso compounds 10a,b (0.3–0.5 mmol)
in THF/H2O (10:1, v/v) at room temp. with stirring. Then HgCl2
at the tip of a spatula was added (exothermic reaction has an induc-
tive period from one to several minutes!). The reaction mixture was
stirred at room temp. until the blue colour disappeared and the
silvery pieces of foil had turned into a grey powder. The inorganic
residue was filtered through Celite 545 and washed with THF
(twice with same volume as the reaction mixture). The combined
filtrate and washings were concentrated, and the residue was puri-
fied by gradient column chromatography (ethyl acetate/hexane as
eluent, from 1:5 to 2:1, v/v). For details, see the Supporting Infor-
mation.
Experiment 2: TBSOTf (0.012 mL, 0.05 mmol) was added to a
stirred solution of nitronates 1a (54 mg, 0.25 mmol) and 3a (44 mg,
0.25 mmol), silyl ketene acetal 4 (45 mg, 0.24 mmol) and 2,6-di-
tert-butyl-4-methylpyridine (21 mg, 0.1 mmol) in CH2Cl2 (2.5 mL)
Reduction of 5a with LiAlH4: A solution of trans-5a (150 mg,
0.41 mmol) in THF (1.0 mL) was added to a stirred solution Li-
at –78 °C and the reaction mixture was stirred at –78 °C for 18 h. AlH4 (15.6 mg, 0.41 mmol) in THF (1.0 mL) under argon at
Then the reaction mixture was quenched at –78 °C by the success-
ive addition of Et3N (0.05 mL, 0.36 mmol) and MeOH (0.005 mL,
0.12 mmol). Further operations are the same as for procedure B
–30 °C, and the reaction mixture was allowed to warm to ambient
temperature. After 1 h at room temp., Na2SO4·10H2O (0.5 g,
1.55 mmol) was added to the reaction mixture, and stirring was
Eur. J. Org. Chem. 2009, 3066–3074
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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