Sulfoxide-mediated Umpolung of alkali halide salts

Article abstract of DOI:10.1039/c2ob25459j

A new protocol for the direct two-electron oxidative Umpolung of alkali halide salts is reported. This procedure, relying on the use of a commercially available sulfoxide as the oxidant, allows the electrophilic halogenation of carbonyl compounds as well as halolactonisation reactions to proceed from the corresponding sodium salts, at room temperature and under mild conditions.

Full text of DOI:10.1039/c2ob25459j

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Chemistry
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Volume 10 | Number 22 | 14 June 2012 | Pages 4301–4472
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S. Klimczyk, N. Maulide et al.
Sulfoxide-mediated Umpolung of alkali halide salts

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Sulfoxide-mediated Umpolung of alkali halide salts†
Sebastian Klimczyk, Xueliang Huang, Christophe Farès and Nuno Maulide*
Received 1st March 2012, Accepted 12th March 2012
DOI: 10.1039/c2ob25459j
A new protocol for the direct two-electron oxidative Umpo-
lung of alkali halide salts is reported. This procedure, relying
on the use of a commercially available sulfoxide as the
oxidant, allows the electrophilic halogenation of carbonyl
compounds as well as halolactonisation reactions to proceed
from the corresponding sodium salts, at room temperature
and under mild conditions.
The substitution of a carbon–hydrogen with a carbon–halogen
Scheme 1 Initial experiment and sulfoxide-mediated redox
chlorination.
bond often has profound implications on the properties of the
resulting organic compound. Interestingly, more than 4000 halo-
genated natural products, displaying a wide range of biological
activities, have been isolated to date.1 Given the broad avail-
ability of halide salts in Nature, a two-electron oxidative Umpo-
lung of halide anions (X− to X+, where X = Cl, Br or I) is a
likely strategy for enzymatic halogenation.2
In preparative chemistry, however, the direct Umpolung of
halides is seldom employed. Typically, reagents like SO2Cl2,3
NXS,4 hypohalide salts5 and others6,7 are used for halogenation.
Formal oxidation of X− has been achieved by V2O5–H2O2–
NH4Br combinations,8 CAN,9 oxone,10 or strong Lewis acids
like AlCl3–Pb(OAc)4 and ZnBr2–Pb(OAc)4 couples.11,12 The
most efficient methods hinge on the use of hypervalent iodine
compounds such as Koser’s reagent,13 (dichloroiodo)toluene14
or (diacetoxyiodo)benzene.15 Nevertheless, processes allowing a
direct Umpolung of the ubiquitous sodium chloride or sodium
bromide under simple conditions are scarce.16 Herein, we report
an Umpolung of simple alkali halides that takes place at room
temperature using a commercially available sulfoxide as the
oxidant.
During our recent investigations on sulfoxide-mediated direct
arylation reactions,17 we found that the combination of β-ketoe-
ster 1a, sulfoxide 2 and trimethylsilyl chloride (TMSCl), as acti-
vating agent did not yield the expected arylation compound 3,
but rather the α-chlorinated ketone 4a and thioanisole (5) as
byproducts (Scheme 1).18
Scheme 2 Scope of the direct Umpolung chlorination of carbonyl
a
compounds 1 using sodium chloride. All yields refer to pure, isolated
b
compounds. Compound 4k was obtained as a 4 : 1 mixture of diaster-
eoisomers. See the ESI† for details and X-ray structures of selected
products.
could be adapted for the direct oxidation of inorganic chloride
salts. A thorough screening of activating agent–salt combi-
nations19 revealed that salts such as LiCl, NaCl, CsCl or CaCl2
were all suitable chloride donors when used in conjunction with
trimethylsilyl triflate (TMSOTf) as the activating agent. Of
further interest was the observation that phenylmethyl sulfoxide
2 afforded up to 10-fold faster reaction times when compared
with DMSO and other sulfoxide reagents.19
In this interesting redox reaction, it appears that TMSCl func-
tions simultaneously as both an activating agent and a chloride
donor. This raised the question of whether such a transformation
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim, Germany. E-mail: maulide@mpi-muelheim.mpg.de
†Electronic supplementary information (ESI) available: Reaction optim-
isation, experimental procedures and characterisation of products. See
DOI: 10.1039/c2ob25459j
With these conditions in hand, the scope and limitations of the
reaction were examined and the results are compiled in
Scheme 2. In addition to six-membered cyclic β-ketoesters, five-,
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Scheme 3 Scope of the direct Umpolung bromination of carbonyl
a
compounds 1 using sodium bromide. All yields refer to pure, isolated
compounds. See the ESI† for details.
Scheme 5 Proposed mechanistic rationale for the sulfoxide-mediated
Umpolung halogenation. See the ESI† for details.
Me3Si-group exhibits NOE contacts and common diffusion con-
stants in NOESY and DOSY spectra, respectively, with the aryl
and methyl groups. Species A lends itself to nucleophilic attack
by the halide anion to form the sulfurane B, an interesting
species which conceptually bears a reasonably strong incipient
base (TMSO−) and a formally electropositive halide. Species B
reacts with the enol substrate 1a′, according to the much steeper
decline of its NMR signals compared those of the keto counter-
part 1a in a kinetic study. This step ultimately leads to the
observed products 4a and sulfide 5. NMR and GC analyses also
identified hexamethyldisiloxane (TMSOTMS) as the ultimate
fate of the TMS group, presumably through dehydro-conden-
sation of TMSOH.
Scheme 4 Dual regioselectivity in the Umpolung bromination of car-
bonyl compounds 1 using sodium bromide or TMSBr. All yields refer
to pure, isolated compounds. See the ESI† for details.
a
seven- and eight-membered compounds underwent chlorination
smoothly in good yields (Scheme 2, 4a–4d). Various β-ketoesters
derived from α-tetralone (4f–h) or 1-indanone (4m–o) provided
the resulting chlorinated products in good to excellent yields.
Furthermore a thiophene bearing compound could be chlorinated
in excellent yield (4i). The reaction is not limited to β-ketoesters,
and simple ketones displayed high reactivity as well.
The corresponding bromination reaction is possible under ana-
logous reaction conditions, employing sodium bromide as the
halogen donor. The brominated compounds 6a–e were obtained
in very good to excellent yields, up to 93% (Scheme 3).
In the case of the bromination reaction, the presence of “free”
bromide anion in solution (from NaBr) presumably allows the
in situ formation of elemental bromine by direct nucleophilic
attack onto the halide terminus of intermediate B. The much
lower bromide concentrations when TMSBr is employed are
likely to render this pathway ineffective. It is interesting to note
that, although the stoichiometric brominations by elemental
bromine depicted in Scheme 4 should theoretically require 2
equivalents of NaBr to reach completion, the fact that bromide
anion (Br−) is released upon halogenation means that this
process is potentially self-sustainable. Accordingly, we observed
full conversion of starting materials and yields superior to 50%
employing a single equivalent of NaBr.
Finally, the conditions described herein were applied to the
halolactonisation of ω-unsaturated carboxylic acids.22 Employing
the TMSOTf–NaBr couple, it was possible to obtain different
bromo-butyrolactones (Scheme 6) in moderate to excellent
yields. The results depicted in Scheme 6 are comparable to those
reported in the recent literature.23
Interestingly, if the substrate bears a methylene (–CH2–) group
in the α′-position, such as in 1a, this bromination reaction takes
a different course (Scheme 4). In these cases, the bromo enols 5
were formed as the exclusive reaction products. Such a drastic
change in regioselectivity is characteristic of a direct reaction
with elemental bromine (Br2), as documented in the literature.20
It is important to note that if TMSBr is employed instead of the
TMSOTf–NaBr couple for the bromination of 1a, the “standard”
regioselectivity is again exclusively observed (Scheme 4). This
key experimental fact suggests that different mechanisms (vide
infra) operate under those two sets of conditions and highlight
the uniqueness of the TMSOTf–sodium salt mixture.
Some mechanistic features for this reaction could be inferred
by combined MS and NMR analysis. We believe that the reac-
tion proceeds through an activated sulfoxide intermediate A
(Scheme 5), which forms in a rapidly interconverting equili-
brium with TMSOTf and sulfoxide 2.21 The presence of this
dynamic species A was deduced through both NMR and ESI
mass spectroscopy. On one hand, the observed NMR high-(low-)
field shifts of the ipso (para) carbon in the aromatic ring suggest
a positive charge at the sulfur position. On the other hand the
In summary, a new procedure for the direct Umpolung of
halides under mild, metal-free conditions was developed. This
reaction allows electrophilic halogenations (including halolacto-
nisations) to proceed directly from the corresponding sodium
salts and relies on the use of a sulfoxide as the net two-electron
oxidant.
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Scheme 6 Direct Umpolung halolactonisation of ω-alkenoic acids
using sodium bromide. All yields refer to pure, isolated compounds.
Compounds 10d/e were obtained as 1 : 1 diastereoisomeric mixtures. See
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a
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We are grateful to the Max-Planck-Society and the Max-Planck-
Institut für Kohlenforschung for generous support of our
research programs. This work was funded by the Deutsche For-
schungsgemeinschaft (DFG Grant MA 4861/4-1). We further
acknowledge Dr R. Goddard (MPI Mülheim) for X-ray structure
determinations and Mr H.-W. Klein (MPI Mülheim) for MS
determinations.
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