10.1002/adsc.201901500
Advanced Synthesis & Catalysis
In a test tube, equipped with a magnetic stir bar, substrates
1 (0.1 mmol) and TBABr (3.2 mg, 0.01 mmol, 10 mol%)
were suspended in toluene (500 μL) and the reaction
mixture was cooled to 0 °C. Then, Cs2CO3 (40.0 mg, 0.12
mmol) and the corresponding nucleophile (0.12 mmol) were
added in this order. The resulting suspension was vigorously
stirred for 1 h at 0 °C, diluted with CH2Cl2 (1 mL), passed
through a small plug of silica, eluted with CH2Cl2 (3x1 mL)
and Et2O (3x1 mL) and evaporated in vacuo. The resulting
crude mixture was analyzed by means of 1H NMR
spectroscopy to calculate the diastereomeric ratio and
finally purified by column chromatography on silica gel
(CH2Cl2/Et2O mixtures) to obtain products rac-3, 4 or 5.
20:1). [α]D25 = -89 (c = 0.7 in CHCl3) for 88% ee. 1H NMR
(600 MHz, CD3CN) δ = 7.62 – 7.59 (m, 2H), 7.48 – 7.44 (m,
2H), 7.41 – 7.33 (m, 5H), 3.88 (ddd, J = 12.0, 4.7, 1.9 Hz,
1H), 3.71 (s, 3H), 3.58 (td, J = 12.0, 4.7 Hz, 1H), 3.50 (dd,
J = 12.2, 1.9 Hz, 1H), 3.40 (bs, 1H), 2.43 (s, 3H), 2.33 (d, J
= 12.4 Hz, 1H), 2.25 (t, J = 11.8 Hz, 1H) partially
overlapped with 2.23 (d, J = 12.2 Hz, 1H). 13C NMR (151
MHz, CD3CN) δ = 171.5, 144.1, 133.5, 132.8 (2C), 132.4,
129.7 (2C), 129.3 (2C), 128.2, 127.5 (2C), 69.1, 55.4, 55.2,
51.5, 50.3, 43.2, 24.9, 20.5. HRMS: calculated for
[C21H25NO5S2 + Na+]: 458.1066; found: 458.1064. HPLC:
OD-H (n-hexane/iPrOH 90:10, flow-rate 1.00 mL/min; tmaj
= 18.4 min; tmin = 30.4 min).
Methyl
(2R*,6S*)-2-(6-cyano-6-methyl-4-
tosylmorpholin-2-yl)acetate 4a. Following the general
procedure from substrate 1a and acetone cyanohydrin,
product 4a (>20:1 dr after column chromatography and in
the crude mixture) was obtained as a white solid in 90%
yield (31. 7 mg) after column chromatography on silica gel
(CH2Cl2/Et2O = 70:1). 1H NMR (400 MHz, CDCl3) δ = 7.73
– 7.64 (m, 2H), 7.40 – 7.32 (m, 2H), 4.41 (dtd, J = 10.6, 6.3,
2.6 Hz, 1H), 3.83 (dd, J = 12.1, 1.6 Hz, 1H), 3.80 – 3.73 (m,
1H), 3.71 (s, 3H), 2.54 (dd, J = 15.9, 6.6 Hz, 1H), 2.45 (s,
3H) overlapped with 2.44 (dd, J = 15.9, 6.0 Hz, 1H), 2.29
(d, J = 12.1 Hz, 1H), 2.23 (dd, J = 11.7, 10.6 Hz, 1H), 1.55
(s, 3H). 13C NMR (101 MHz, CDCl3) δ = 169.4, 144.5,
132.6, 130.0 (2C), 127.8 (2C), 117.7, 70.6, 70.3, 52.6, 52.1,
48.3, 37.6, 24.3, 21.6. HRMS: calculated for [C16H20N2O5S
+ Na+]: 375.0985; found :375.0991.
Acknowledgements
We acknowledge financial support from the University of Bologna
(RFO program), MIUR (FFABR 2017), and F.I.S. (Fabbrica
Italiana Sintetici). We thank Luca Zuppiroli (University of
Bologna) for the HRMS analyses. We also thank Costanza
Leonardi, Ana Ubide Botella, Eleonora Ridolfini and Pietro Viola
for preliminary investigations and preparation of the starting
materials.
References
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1
chromatography on silica gel (CH2Cl2/Et2O = 60:1). H
NMR (400 MHz, DMSO-d6) δ = 7.71 – 7.61 (m, 2H + 2H),
7.51 – 7.40 (m, 2H + 2H), 6.93 (s, 1H), 6.72 (s, 1H), 4.02 –
3.87 (m, 1H + 1H), 3.66 (dd, J = 12.2, 1.1 Hz, 1H) partially
overlapped with 3.65 (s, 3H), 3.64 (s, 3H), 3.50 (dd, J = 12.2,
1.5 Hz, 1H), 3.01 (dddd, J = 11.2, 7.3, 6.1, 3.9 Hz, 1H), 2.82
(dddd, J = 10.8, 7.6, 5.4, 4.2 Hz, 1H), 2.63 – 2.52 (m, 2H +
2H), 2.40 (s, 3H), 2.39 (s, 3H) partially overlapped with
2.398 (d, J = 12.6 Hz, 1H), 2.31 (d, J = 12.7 Hz, 1H), 2.27
– 2.10 (m, 1H +1H), 1.50 (s, 3H), 1.45 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ = 170.5, 170.4, 144.7, 144.4, 133.2,
132.8, 130.6 (2C), 130.5 (2C), 127.9 (2C), 127.8 (2C), 114.2,
114.0, 113.1, 112.8, 71.7, 71.2, 53.2, 52.51, 52.48, 52.2,
50.8, 48.6, 46.6, 46.1, 37.0, 35.3, 34.3, 34.2, 24.3, 22.8,
21.49, 21.46. All peaks are given without assignation.
HRMS: calculated for [C18H21N3O5S - H+]: 390.1129;
found :390.1124.
General Procedure for the synthesis of enantioenriched
piperidines 3.
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Catalysts 2018, 8, 632: doi:10.3390/catal8120632.
In a test tube, equipped with a magnetic stir bar, substrates
1 (0.1 mmol) and catalyst G (6.4 mg, 0.01 mmol, 10 mol%)
were suspended in toluene (2 mL) and the reaction mixture
was cooled to 0 °C. Then, Cs2CO3 (40.0 mg, 0.12 mmol)
and the corresponding thiophenol (0.12 mmol) were added
in this order. The resulting suspension was vigorously
stirred for 1 h at 0 °C, diluted with CH2Cl2 (1 mL), passed
through a small plug of silica, eluted with CH2Cl2 (3x1 mL)
and Et2O (3x1 mL) and evaporated in vacuo. The resulting
crude mixture was analyzed by means of 1H NMR
spectroscopy to calculate the diastereomeric ratio and
finally purified by column chromatography on silica gel
(CH2Cl2/Et2O mixtures) to obtain products 3 as white
amorphous solids.
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Chem. Eur. J. 2015, 21, 17578-17582.
Methyl (3S,4S,5S)-3-hydroxy-3-methyl-5-(phenylthio)-
1-tosylpiperidine-4-carboxylate 3aa
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Following the general procedure from substrate 1a and
thiophenol 2a, product 3aa (>20:1 dr after column
chromatography, 8:1 in the crude mixture) was obtained as
a white solid in 80% yield (34.8 mg) after column
chromatography on silica gel (CH2Cl2/Et2O = from 50:1 to
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of type 1 in domino reactions, see: a) D. F. Cauble, J. D.
8
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