COMMUNICATION
Table 1. Ligand screening for an asymmetric sulfoxide–magnesium
exchange.[a]
symmetrizes dibromo sulfoxide 8a as well (! 7a + iPrBr).
In 8a, an S(=O) group assumes the same location—a
bridge—and conceivably the same role—of a Lewis base,
which by virtue of its donating oxygen atom coordinates an
organomagnesium compound—as the C(Oꢁ)H unit of de-
protonated 5.
Although we expected the intended bromine–magnesium
exchange to proceed relatively fast,[21] exposing 8a in THF
solution to essentially the same conditions as 5,[22] that is to
slight excesses both of MgHal2-free iPr2Mg[23] and the lithi-
um salt (Li-11) of the monomethyl ether (11)[24] of (S)-
BINOL (ꢀ408C, 20 min) we obtained none of the expected
diaryl sulfoxide 7a but 25% isopropyl phenyl sulfoxide
(+)-(R)-9b and 57% bromoisopropyl phenyl sulfoxide
(+)-(R)-9a (Scheme 1, middle). This suggested that a selec-
tive sulfoxide–magnesium exchange[25] had occurred first (!
9a) and that a bromine–magnesium exchange in some of the
primary product had followed (9a ! 9b). Such a rate order
sulfoxide–magnesium exchange > bromine–magnesium ex-
change was reported for a biphenyl with a 4-(Me2N)C6H4-
S(=O), a Br, and a remote Cl substituent.[25e] The sulfoxide–
magnesium exchange product 9a had an ee of 19% and its
follow-up product 9b an ee of 4%. These data meant that
the sulfoxide–magnesium exchange in substrate 8a had oc-
curred with some enantioselectivity. This selectivity was
modified through the subsequent bromine–magnesium ex-
change. Still, the lower yield and the lower enantiopurity of
follow-up product (+)-(R)-9b relative to the yield and the
enantiopurity of the primary product (+)-(R)-9a implied
that the non-racemic composition of (+)-(R)-9a was due
mostly to an asymmetric sulfoxide–magnesium exchange in
8a and to a lesser extent to a configuration-dependent bro-
mine–magnesium exchange in 9a. This is correctly stated be-
cause the yield of (+)-(R)-9a would have been 82% and its
enantiomeric excess 14% if none of it had proceeded to
XMg-(+)-(R)-9b.[26] To the best of our knowledge such a de-
symmetrization of any diaryl sulfoxide 8 has not been re-
ported yet. We have improved this unprecedented transfor-
mation with the brominated diaryl sulfoxide 8a and extend-
ed it to nine bromine-free diaryl sulfoxides 8b–j.
Entry
Ligand
9c
Yield [%]
% ee
1
2
(ꢀ)-menthol
(ꢀ)-borneol
11
rac
rac
R
rac
rac
S
S
S
S
83
92
96
87
90
70
31
89
86
<1
<1
13
<1
<1
65
27
3
3[b]
4
T
5
6
ACHTUNGTRENNUNG
12
12
13
7[c]
8
9[d]
(ꢀ)-pseudoephedrine
3
[a] Ligand (1.5 equiv), THF, nBuLi (1.0 equiv or 2.0 equiv for ligands
with one or two acidic protons), 08C, 10 min; 228C, 10 min; iPr2Mg[23]
(1.2 equiv), 10 min; ꢀ408C, 8c, t1 =20 min. [b] t1 was increased to 40 min.
[c] iPrMgBr·LiCl[28] (1.2 equiv) was employed instead of iPr2Mg. [d] t1
was increased to 30 min. [e] TADDOL=a,a,a’,a’-tetraaryl-1,3-dioxolan-
4,5-dimethanol.
instead of 12 to become the chiral auxiliary the enantiocon-
trol almost vanished (89% yield, 3% ee; Table 1, entry 8).
Keeping with iPr2Mg (1.2 equiv), Li2-12, and sulfoxide 8c,
premixing iPr2Mg and Li2-12 at 228C for 10 min, and leaving
the sulfoxide–magnesium exchange time constant [90 min,
with one exception (Table 2, entry 5)] we optimized 1) the
exchange temperature T1, 2) the ligand/substrate ratio, and
3) the solvent—to the extent summarized in Table 2. The re-
sulting sulfoxide 9c was uniformly levorotatory. In the pres-
ence of 1.5 equivalents of ligand Li2-12 the best yield (90%)
and highest enantioselectivity (74% ee) resulted from mag-
nesium uptake at T1 =ꢀ788C. The sulfoxide–magnesium ex-
change worked best if 3.0 equivalents of Li2-12 were present
(97% yield, 78% ee). Changing the solvent affected the
enantioselectivity adversely (Table 2, entries 13–16 vs. 12).
The reagents from Table 1 (iPr2Mg and Li2-12) and the re-
action conditions from Table 2 (1.5 or 3.0 equivalents of
ligand) provided good guidance for desymmetrizing a varie-
ty of diaryl sulfoxides (Table 3). Still, depending on the sub-
strate, some adaptations were called for. The toughest case
was realizing no more than a chemoselective sulfoxide–mag-
nesium exchange in bis(2-bromophenyl) sulfoxide (8a). This
was because a bromine–magnesium exchange in the desired
product (ꢀ)-9a doomed (cf. the facile over-reaction of 9a
and iPr2Mg leading to 9b; Scheme 1) and had to be sup-
pressed. Extensive experimentation allowed to access (ꢀ)-
(S)-9a in 70% yield and with 36% ee (Table 3, entry 1). The
other diaryl sulfoxides 8b–j of Table 3 underwent asymmet-
We began our investigations with the readily accessible
bisACHTUNGTRENNUNG
(4-tolyl) sulfoxide (8c)[27] (Table 1). We subjected this
substrate to sulfoxide–magnesium exchanges either with
1.2 equivalents of iPr2Mg (Table 1, entries 1–6, 8, 9) or with
1.2 equivalents of iPrMgBr·LiCl[28] (Table 1, entry 7), always
in the presence of 1.5 equivalents of a fully deprotonated
enantiomerically pure alcohol, phenol, diol or binaphthol
(Table 1, entries 1–8); one amino alcohol was used similarly
(Table 1, entry 9). iPr2Mg and the dilithium salt (Li2-12) of
(S)-BINOL (12) were the by far best ligand/reagent combi-
nation for inducing enantioselectivity (Table 1, entry 6).
After 20 min at ꢀ408C the substrate 8c was completely con-
sumed and the unsymmetrical sulfoxide (ꢀ)-(S)-9c was ob-
tained in 70% yield and with 65% ee. Using iPrMgBr·LiCl
and Li2-12 instead of iPr2Mg and Li2-12 caused yield (31%)
and enantioselectivity (27% ee) losses (Table 1, entry 7).
When the bulkier BINOL derivative 13[29] was deprotonated
Chem. Eur. J. 2012, 18, 3136 – 3140
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3137