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1504
P. Kelly et al.
LETTER
Sample temperature control was maintained using a Julabo F25-
MV immersion circulator. Results were processed on a Dell
Optiplex GX260 PC using Bio Light Pol Winlab software (version
number 1.00.01). The units of a are 10–1 deg cm2g–1. Absolute con-
figurations were assigned by the comparison of the specific rota-
tions with the literature data (7b,d,g,i–k) or comparison of HPLC
retention times with enantiopure samples of known configuration
(7l). Notably, the direction of the specific rotations were in com-
plete agreement with literature values, however, the magnitudes
varied somewhat.
Sulfoxides 7a,22 7c22 and 7e23 have been previously reported in
racemic form only. Sulfoxides 7b,d,g,i–k have been reported in
enantioenriched form.14b Sulfoxides 7f,h,l have not been previously
reported.
The use of dimethyl sulfoxide (DMSO) as an additive
resulted in a slight improvement in enantioselectivity
(Table 2, entry 2) while using the ionic liquid, 1-butyl-3-
methylimidazolium hexafluorophosphate, as an additive
resulted in a further improvement in the enantioselectivity
of the oxidation (Table 2, entry 3).
Again, introducing a methoxy substituent into the aryl
ring showed interesting trends with the enantioselectivity
increasing as the methoxy group moves from the para to
meta to ortho positions (Table 2, entries 7–9). Enantiopu-
rities of up to 81% ee can be achieved albeit in modest
yield (Table 2, entry 9). Presumably, a copper–Schiff
base–oxo complex mediates this oxidation, however, no
investigation was undertaken to establish the nature and Typical Experimental Procedure
Copper(II) acetylacetonate (2.6 mg, 2.0 mol%) was added to a
structure of this complex.
round-bottomed flask containing 2 (15.2 mg, 4.0 mol%) and CCl4
(1 mL). The resulting solution was stirred at r.t. for 5 min, and then
a solution of 6 (1 mmol) in CCl4 (1 mL) was added. After 5 min stir-
ring at r.t. NMO (3 mg, 2.5 mol%) was added to the reaction mix-
ture and after stirring for a further 5 min at r.t. H2O2 (0.11 mL, 30%,
1.1 mmol) was added in one portion, dropwise to the solution. The
reaction mixture was then stirred at r.t. for a further 16 h. Then, H2O
(5 mL) was added and the phases separated; the organic layer was
washed with H2O (2 × 5 mL) and brine (5 mL), dried, and concen-
trated at reduced pressure to give the crude product. The ratio of 6:7
in the crude product was determined by 1H NMR. The product was
The results reported above reflect the highest enantio-
selectivities to date in copper-catalysed asymmetric
sulfide oxidation. While the results obtained using this
method are modest in comparison to other established
asymmetric sulfide oxidation methods, critically no
sulfone formation occurs under these conditions. Over-
oxidation leading to sulfone formation often accompanies
asymmetric sulfide oxidation. In some cases the formation
of the sulfone may be the result of kinetic resolution
which can enhance the overall enantioselectivity of the purified by column chromatography on silica gel (6:4, hexane–
oxidation.14,21 However, the presence of sulfone in the
EtOAc).
crude product can make isolation of the pure sulfoxide te-
dious. Sulfone formation also impacts deleteriously on the
overall yield of the oxidation. Using an achiral ligand it is
(R)-(+)-Benzyl-4-fluorophenyl Sulfoxide (7a, Table 2, Entry 4)22
Crude product contained a mixture of sulfide and sulfoxide (71:29).
Purification by chromatography afforded the product as a white
possible to use this methodology for the chemoselective
preparation of racemic sulfoxides. Furthermore, the sensi-
tivity of the asymmetric sulfide oxidation to the precise
structure of the aryl benzyl sulfide is indicative of signifi-
cant ligand–substrate interactions in the transition state
for the oxidation. Therefore, improvement of this method
either through ligand modification or the screening of
further additives could lead to enhanced enantioselection
coupled with high chemoselectivity for sulfoxide forma-
tion.
solid (49 mg, 21%, 40% ee).
1H NMR: d = 3.90–4.02 (1 H, A of ABq, J = 12.5 Hz, one of
SOCH2), 4.08–4.21 (1 H, B of ABq, J = 12.5 Hz, one of SOCH2),
6.92–6.99 (2 H, m, ArH), 7.11 (2 H, t, J = 8.5 Hz, ArH), 7.21–7.39
(5 H, m, ArH). HPLC: tR (R) = 34.5 min, tR (S) = 39.9 min [Chiracel
OD-H; flow rate 1.0 mL min–1; hexane–2-PrOH (98:2); 20 °C];
[a]D20 +60 (c 0.19, acetone).
(R)-(+)-Benzyl-4-bromophenyl Sulfoxide (7b, Table 2, Entry
5)14b
Crude product contained a mixture of sulfide and sulfoxide (72:28).
Purification by chromatography afforded the product as a white
solid (59 mg, 20%, 37% ee).
Chemicals and solvents were purchased from commercial suppliers.
Sulfides 6a–c and 6e–l were prepared by treatment of an excess of
thiolate anion with the appropriate benzyl halide. Sulfide 6d was
purchased from Aldrich. For thin-layer chromatography (TLC),
Merck 60 F254 silica gel plates were used and compounds were vi-
sualised by UV. Solvents were distilled before use. 1H NMR (300
MHz) and 13C NMR (75.5 MHz) spectra were recorded on a Bruker
AVANCE300 at 20 °C using CDCl3 as solvent. Chemical shifts are
given in ppm relative to TMS as the internal standard. Coupling
constants (J) are reported in Hz. Mass spectra were recorded on a
Waters/Micromass LCT Premier Time of Flight spectrometer (ESI)
and a Waters/Micromass Quattron Micro triple quadrupole spec-
trometer (ESI). Chiral HPLC was performed with a Waters 600E
System Controller and a Waters 996 Photodiode Array Detector op-
erating a Chiralpak OD-H column from Daicel Chemical Industries
Ltd., eluting with n-hexane and 2-PrOH. Specific rotations were re-
corded on a Perkin Elmer 341 polarimeter, at 20 °C in the solvents
indicated. The sodium D-line (589 nm) was used unless otherwise
indicated. Samples were analysed in a 1 mL dual-walled, thermo-
statted glass cell (PE part number: 631136) of path length 10 cm.
1H NMR: d = 3.90–4.02 (1 H, A of ABq, J = 12.6 Hz, one of
SOCH2), 4.05–4.16 (1 H, B of ABq, J = 12.6 Hz, one of SOCH2),
6.94–7.01 (2 H, m, ArH), 7.15–7.35 (5 H, m, ArH), 7.51–7.61 (2 H,
m, ArH). HPLC: tR (R) = 44.4 min, tR (S) = 50.1 min [Chiracel OD-
20
H; flow rate 0.5 mL min–1; hexane–2-PrOH (94:6); 10 °C]; [a]D
20
+39.6 (c 0.37, CHCl3); lit. 14b: [a]D –65 (c 0.2, CHCl3) for S
>99% ee.
(R)-(+)-4-Fluorobenzyl-4¢-fluorophenyl Sulfoxide (7c, Table 2,
Entry 6)22
Crude product contained a mixture of sulfide and sulfoxide. Purifi-
cation by chromatography afforded the product as a white solid (65
mg, 26%, 52% ee).
1H NMR: d = 4.00 (2 H, s, SOCH2), 6.89–6.97 (4 H, m, ArH), 7.12–
7.21 (2 H, m, ArH), 7.30–7.39 (2 H, m, ArH). HPLC: tR (R) = 34.5
min, tR (S) = 39.9 min [Chiracel OD-H; flow rate 1.0 mL min–1;
hexane–2-PrOH (98:2); 20 °C]; [a]D20 +46.7 (c 0.38, acetone).
Synlett 2007, No. 10, 1501–1506 © Thieme Stuttgart · New York
Kelly, Pádraig
