Prochiral Diheteroaryl Sulfoxides and Their Reactions with (S)-Li2-BINOLate-Activated Diisobutylmagnesium

Article abstract of DOI:10.1002/ejoc.201701309

5-Membered ring heterocycles were α-lithiated or α-magnesiated so that they attacked SOCl₂ or SO(OMe)₂ forming symmetric – i.e. prochiral – diheteroaryl sulfoxides. The latter were treated with a 0.5- or 1.2-fold molar amount of 5:4 mixtures of dilithium (S)-BINOLate and diisobutylmagnesium. This allowed five asymmetric sulfoxide/magnesium exchange reactions to occur. They delivered asymmetric sulfoxides in up to 77 % yield and with up to 88 % ee. Surprisingly, four related diheteroaryl sulfoxides, bis(2-pyridyl) sulfoxide, and bis(3-pyridyl) sulfoxide were unamenable to such exchanges and decomposed instead.

Full text of DOI:10.1002/ejoc.201701309

A Journal of
Accepted Article
Title: Prochiral Diheteroaryl Sulfoxides and Their Reactions With (S)-
Li2-BINOLate-Activated Diisobutylmagnesium
Authors: Reinhard Brückner and Simon Ruppenthal
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701309
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701309
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European Journal of Organic Chemistry
10.1002/ejoc.201701309
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(
(For Table of Contents:))
Key Topic: Desymmetrizations
S. Ruppenthal, R. Brückner*
Prochiral Diheteroaryl Sulfoxides and Their Reactions With (S)-Li
BINOLate-Activated Diisobutylmagnesium
2
-
O
S
O
5
:4 mixture of
S
or other products
= best result
Heteroaryl
Heteroaryl
Heteroaryl (S) iBu
Li
O
O
O
MOM
Li
S
N
(
S) iBu (71%, 88% ee)
and iBu
2
Mg
in THF, −78°C
2
An α-metalation of nine 5-membered ring heterocycles followed by treatment with SOX (X = Cl, OMe) provided the respective
diheteroaryl sulfoxides. They were exposed to a mixture of dilithium (S)-BINOLate and diisobutylmagnesium at −78°C for bringing about
an asymmetric sulfoxide/magnesium exchange. This provided unsymmetric sulfoxides in up to 77% yield and with up to 88% ee.
However, a number of related substrates did not react analogously.
1
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European Journal of Organic Chemistry
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Prochiral Diheteroaryl Sulfoxides and Their Reactions With (S)-
Li -BINOL-Activated Diisobutylmagnesium
2
[a]
[a]
Simon Ruppenthal and Reinhard Brückner*
and best administered as the (S)-enantiomer.[5] The (S)-
enantiomer of ZD3638 (2) – a discontinued lead-compound from
AstraZeneca – acts against migraine and schizophrenia.[6] The
(S)-enantiomer of OPC-29030 (3) is hypocholesterolemic.[7,8]
Fipronil (4) is a BASF insecticide.[9] While applied as a racemic
mixtures, the constituting enantiomers differ in vivo.[10] A stand-
Abstract: 5-Membered ring heterocycles were α-lithiated or α-
magnesiated so that they attacked SOCl or SO(OMe) forming
2
2
symmetric − i. e. prochiral − diheteroaryl sulfoxide. The latter were
treated with a 0.5- or 1.2-fold molar amount of 5:4 mixtures of
dilithium (S)-BINOLate and diisobutyl magnesium. This allowed
five asymmetric sulfoxide/magnesium exchange reactions to
occur. They delivered unsymmetric sulfoxides in up to 77% yield
and with up to 88% ee. Surprisingly, four related diheteroaryl
sulfoxides, bis(2-pyridyl) sulfoxide, and bis(3-pyridyl) sulfoxide
were unamenable to such exchanges and decomposed instead.
alone but fascinating application of an enantiomerically pure
sulfoxide is in one of Feringa´s unidirectional motors.[11]
O
O
ref.[16,17]
S
S)
S
Arylpro-(R)
Arylpro-(S)
Aryl ( Alkyl
Introduction
5
6
(
up to 97% ee)
+
Sulfoxides are important compounds.[1] Their S-atom is pyrami-
dalized whereby it becomes a stereocenter in unsymmetric sulf-
oxides. Sulfoxides with a homogeneously configured S-atom are
versatile aids in asymmetric synthesis[2] including asymmetric
AlkylMg Arylex-pro-(S) (8)
Li
O
O
dialkyl sulfoxide
(7; undesired)
Alkyl
2
Mg +
+
Li
catalysis.[3] Several alkyl heteroaryl sulfoxides, whose S-atom is
AlkylMg Heteroarylex-pro-(S) (8')
Li -9
stereogenic − are pharmaceuticals or agrochemicals[4] (Figure 1).
2
O
O
S
Of them, AstraZeneca´s esomeprazole (1) is an anti-ulcer drug
S
Heteroarylpro-(R)
Heteroarylex-pro-(S)
Heteroaryl ( Alkyl
S)
this work
(Alkyl = iBu)
5'
6'
Me
O
N
Scheme 1. Established technique (top): Asymmetric syntheses of alkyl aryl
Objective of current study
bottom): Asymmetric syntheses of alkyl heteroaryl sulfoxide sulfoxides 5’ −
simplified models of compounds 1-4 (Figure 1) − from heterocyclic diaryl
sulfoxides 6’.[
H
sulfoxides 5 from isocyclic diaryl sulfoxides 6.[
16,17]
N
S
H
O
N
OMe
(
S)
O
(
N
S
S)
N
Me
(
18]
MeO
Me
1
: (
−
)-esomeprazole[6]
2: (−
)-ZD3638[7]
Many methods provide chiral sulfoxides enantiomerically pure.[12]
The most common access is by the asymmetric oxidation of un-
symmetric thioethers.[12] Alternative syntheses are based on the
sulfinylation of organometallics.[12] Unusual sulfinylating agents of
that kind are sulfoxides.[13,14,15] The leaving group, which is ex-
O
Cl NH O
2
S
O
F
3
C
S
N
CF3
(
S)
N
N
(
R)
N
N
O
CN
Cl
H
: (+)-(S)-OPC-29030[8]
4: (−)-(R)-fipronil[10]
pelled after the organometallic attacks the S-atom and thereby
3
4
forms a λ -sulfurane, is a different organometallic; it persists until
Figure 1. Biologically active heteroaryl alkyl sulfoxides 1-4.
it is quenched − usually during workup. The top of Scheme 1
illustrates our recent variation of this strategy: the asymmetric
sulfinylation of mixtures of dialkyl magnesium compounds and
[a]
M. Sc. Simon Ruppenthal, Prof. Dr. R. Brückner
Institut für Organische Chemie
2
dilithio-(S)-BINOL (Li -9) with symmetric isocyclic diaryl sulfox-
ides 6.[16,17] This provided alkyl aryl sulfoxides 5 in up to 100%
yield with up to 97% ee. The bottom of Scheme 1 depicts the goal
of the present study: to devop analogous sulfinylations which
would turn symmetric heterocyclic diaryl sulfoxides 6’ into
enantiomerically pure sulfoxides 5’. Either strategy involves
Albert-Ludwigs-Universität Freiburg
Albertstraße 21, 79104 Freiburg, Germany
E-mail: reinhard.brückner@organik.uni-freiburg.de
Supporting information for this article is given via a link at the end of
the document.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
symmetric diaryl sulfoxides as sulfinylating agents, dialkylmag-
nesium compounds as pre-nucleophiles, and Li
Li -8) both as a promoter and inducer of enantiocontrol. The best-
performing dialkylmagnesium of our earlier investigation was
iBu
Mg.[17] Therefore, we stayed with it here, too.
2
-(S)-BINOLate
(
2
2
Br
.
S
c) iPrMgCl LiCl;
N
N
N
O
SOCl2
N
S
BnMgCl;[19]
N
Bn
21
22 (8%)
10
11
7
1%
O
S
O
d) nBuLi;
O
O
HO
Me
O
S
OAc
SOCl2
N
N
EtMgBr;[20]
N
23 (12%; ref.[26]: 59%)
12
13
5
7%
Me
O
O
S
N
S
S
S
S
e) nBuLi;
PhMgBr[21]
N
O
S
Et
SOCl2
14
+
Ph
Et
2
4 (13%; ref.[26]: 0%)
15 (56%)
16 (30%)
PhO S
PhO S
O
S
SO Ph
2
Scheme 2. Selected reactions of pyridyl sulfoxides with Grignard reagents other
than (top and center) – or besides (bottom) – a sulfoxide/magnesium-exchange.
2
2
N
f) LTMP;
SOCl2
N
N
(
ref.[28]
)
25 (50%)
(
)
( )
( )
Depending on the viewpoint, the transformations 6 ‘ → 5 ‘ + 8 ‘
of Scheme 1 represent nucleophilic substitutions at sulfur (cf.
O
S
ref.[14a]), ligand exchanges at sulfur (cf. ref.[14b,c]) or sulfoxide/mag-
nesium exchanges (cf. ref.[14d]). According to the literature,
S
S
S
g) nBuLi;
though, at least pyridyl sulfoxides and Grignard reagents display
a reaction manifold with another three – if not more[18] – overall
SOCl2
26 (32%; ref.[26]
: 34%)
transformations. In Scheme 2 they are exemplified by the reac-
PhO S
PhO S
O
S
SO Ph
2
2
2
tions 10 →11, 12→13,[20] and 14→15.[21] Their products look as
)
[19]
N
N
N
h) nBuLi;
if they originated from an Ar-S reaction, an α-elimination from the
N
sulfinyl group [or “ligand coupling” (notion: ref.[18a,19,21,22])], and
several “sequential transformations” (notion: ref.[23]), respectively.
SOCl2
(ref.[29]
)
27 (79%)
The effective nucleophile of the current study forms from iBu
2
Mg
MOM
MOM
O
S
MOM
N
(
vide supra) and Li -9. Appearing more nucleophilic than RMgHal,
2
N
N
all literature experiences concerning the latter had no direct bear-
ing on the feasibility of our sulfoxide syntheses 6‘ → 5‘ + 8‘ of
Scheme 1.
i) nBuLi;
SO(OMe)2
(
ref.[30]
)
28 (67%)
Boc
Boc
O
S
Boc
N
N
N
j) tBuLi;
Diheteroaryl Sulfoxide Syntheses
SOCl2
(
ref.[31]
)
29 (87%)
We accessed the prochiral diheteroaryl sulfoxides in two ways
(
(
Scheme 3): by oxidizing the respective diheteroaryl sulfide
19[24a] → 20[24a]; 47%) or by sulfinylating metaloheterocycles with
MOM
MOM
O
S
MOM
N
N
N
.
SOCl
% (22) and 87% (29).[25] Occasional literature precedents[26] for
such sulfinylations either were not reached (23: 12% yield; ref.[26]:
2
(in general) or SO(OMe)
2
(preparing 28) in yields between
k) TMPMgCl LiCl;
N
N
N
8
SOCl2
(ref.[32])
30 (31%)
4
5%)] or met (26: 32% yield; ref.[26]: 34%) or surpassed (24: 13%
PhO2S
PhO2S
O
S
SO2Ph
N
yield; ref.[26]: 0%).
N
N
The metalloheterocycles underlying the sulfinylations of Scheme
l) LTMP;
SOCl2
N
N
N
3
stemmed from a Br/Mg-exchange in bromopyridine 21 or from
deprotonations executed with nBuLi, tBuLi, LTMP or
TMPMgCl LiCl[27]. NH-containing heterocycles were N-protected
by known procedures[28-33] before we metalated.
(ref.[33]
)
31 (22%)
.
Scheme 3. Synthesis of the heterocyclic diaryl sulfoxides of this study.
Reagents and conditions: a) NaOH (1.5 equiv.), EtOH, room temp., 30 min;
evaporation of the solvent; 18 (1.0 equiv.); dimethylacetamide, reflux, 72 h; b)
3
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European Journal of Organic Chemistry
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FULL PAPER
mCPBA (1.0 equiv.), CH
2
Cl
2
,
0°C, 17 h; c)-l) heterocycle (2.0 equiv.),
formed THF solution of 1.2 equiv. of iBu Mg and 1.5 equiv. of Li -
2
2
deprotonating agent (2.0 equiv.), THF, usually −78°C for 0.5-1 h (details:
Experimental Part); sulfinylating agent (1.0 equiv.), usually −78°C for 30 min
and then quenched; sometimes warmed to room temp. and quenched after 0.5-
9
. This procedure had worked best starting from isocyclic diaryl
sulfoxides.[17] “Treatment B” was like “treatment A” but confined to
the stoichiometrically required amount of 0.5 equiv. of iBu Mg in
a 4:5 mixture with Li -9.
1
h (details: Experimental Part).
2
2
The eleven sulfoxides disappeared completely under both
reaction conditions (Scheme 4). However, six of them did not
deliver the respective isobutyl sulfoxide (32, 33, 36, and 40-42).
They gave no other discernible product either, e. g., no biaryl
Sulfoxide/Organomagnesium Reactions
2
iBu Mg
premixed in THF with
(
N
from an S 2 reaction or a “ligand coupling”; cf. above) nor
O
S
O
diisobutyl sulfoxide (= compound 7 of Scheme 1 with Alkyl = iBu).
S
*
Heteroaryl
Heteroaryl
Heteroaryl
iBu
Two sulfoxides disappeared as tracelessly during one kind of
Li
“
treatment”; however, they gave the respective isobutyl sulfoxide
O
O
2
0, 22-31
Li -9
34, 35, 37-39
2
(
key: Scheme 3)
(35, 38) after the other “treatment”. In contrast, the isobutyl
sulfoxides 34, 37, and 39 resulted both from “treatment A” and
in THF
Li
,
“
treatment B”.
−
78°C, 10 min − 2.5 h
The eight sulfoxide/magnesium exchange reactions which
worked allright gave yields of 44-77% and ee´s of 15-88%. The
last-mentioned result refers to the MOM-proteced indole sulfoxide
treatment A (upper line):
iBu Mg (1.2 equiv) and
-(S)-BINOLate (1.5 equiv.)
treatment B (lower line):
iBu Mg (0.50 equiv) and
2
2
39. It was isolated in 71% yield. The outcomes of executing
Li
2
Li
2
-(S)-BINOLate (0.63 equiv.)
“
treatment A” vs. “treatment B” differed most from one another for
O
S
O
S
making the furyl isobutyl sulfoxide 34. “Treatment A” gave a
racemic mixture in 88% yield, whereas “treatment B” led to 46%
yield and 45% ee.
N
iBu
N
iBu
3
2
33
The structure variations in the isobutyl sulfoxides which we ob-
tained (34, 35, 37-39) or did not obtain (32, 33, 36, and 40-42)
reveal no structure/reactivity relationships at present.
O
O
O
S
2
PhO S
O
S
S
S
*
N
iBu
iBu
iBu
(
−)-(S[a])-34
0 min, 82%, rac
(−)-35
decomposition
20 min, 64%, 52% ee
36
3
Configurational Assignments
[b]
[b]
3
0 min, 46%, 45% ee
Four (34, 35, 37, 39) of the heteroaryl isobutyl sulfoxides obtained
according to Scheme 4 revealed enantiopurities (45-88% ee)
which warranted elucidating their absolute configuration. For the
sulfoxides 34, 37, and 39 this was accomplished by the ste-
reochemical correlations of Scheme 5. They meant replacing a
furyl, benzothiophenyl or indole moiety through “ligand exchange”
(see above) with excess PhMgCl by a phenyl group.[34] In either
instance, a levorotatory heteroaryl isobutyl sulfoxide reacted to
give the dextrorotatory enantiomer of isobutyl phenyl sulfoxide
O
O
O
PhO
2
S
N
MOM
S
S
S
*
N
S
iBu
iBu
iBu
−)-(S[a])-37
5 min, 64%, 52% ee
0 min, 77%, 47% ee
(+)-38
2.5 h, 44%, 15% ee
(−)-(S[a])-39
50 min, 72%, 77% ee
45 min, 71%, 88% ee
(
[
b]
[b]
[b]
[b]
1
1
[b]
4.5 h, trace
Boc
O
S
MOM
O
S
2
PhO S
O
S
(
43). This succeeded in 30% (45% ee), 80% (40% ee), and 79%
N
N
N
iBu
iBu
iBu
yield (68% ee), respectively. The respective ee values, although
slightly lower than in the substrate indicate that the mentioned
heteroaryl/phenyl exchange reactions had been stereoselective.
Sulfoxides are known to ligand-exchange with organometallics
such that the configuration of their S-atom inverts.[35] Since,
moreover, (+)-isobutyl phenyl sulfoxide (43) equals (R)-43 its
precursor sulfoxides (−)-34, (−)-37, and (−)-39 must have been
N
N
4
0
41
42
Scheme 4. Product portfolio after teating the diheteroaryl sulfoxides 20 and 22-
1 of Scheme 3 with an excess (“treatment A”) or a stoichiometric amount
“treatment B”) of a 5:4 mixture of Li -9-activated with iBu Mg. Sulfoxides shown
in grey were not identified although their respective precursor vanished
instantaneously under the reaction conditions; no other product was isolable
either.− [ Configurational assignment: Scheme 5; [b]ee values: by chiral HPLC
3
(
2
2
a]
(
S)-configured.
(
details: Experimental Part).
The diheteroaryl sulfoxides 20 and 22-31 were exposed at −78°C
as THF solutions to an equimolar amount of a 5:4 mixture of Li
S)-BINOLate (Li -9; Scheme 4) and iBu Mg. We allowed to react
2
-
(
2
2
at −78°C until the sulfoxide was gone, which required 10 min - 2.5
h. With each sulfoxide we tested two sets of conditions.
“
Treatment A” consisted of adding a sulfoxide solution to a pre-
4
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European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
MgCl (2.5 equiv.),
NMR Assignments were made using a combination of 1D and 2D
techniques (DQF-COSY, ed-HSQC, and HMBC). High-resolution mass
spectra: These spectra were obtained in CI/NH (110 eV) or ESI (spray
3
O
O
THF, room temp.,
2.5 h
O
S
S
S
*
iBu
iBu
1
.5 h;
voltage: 4-5 kV) mode, using an orbitrap analyzer. Elemental analyses:
Analyses were obtained on a CHNS analysator. Melting points are
uncorrected and were determined using open glass capillaries. IR spectra
were measured with an FT-IR spectrometer irradiating sample films spread
on a NaCl plate. The ee values were determined by chiral HPLC. Optical
rotations were measured at 365, 436, 546, 578, and 589 nm at 20°C and
were calculated by the Drude equation {[α] = (αexp × 100)/(c × d)}; rotational
values are the average of five measurements of αexp in a given solution of
the respective sample.
30% (45% ee)
(
(
−)-(S)-34
45% ee)
(−)-35
(52% ee)
O
S
iBu
(
+)-(R)-43
O
O
MOM
S
S
2.5 h;
1.5 h;
79% (68% ee)
N
S
iBu
iBu
80% (40% ee)
Preparation of Reactants
dto.,
(−)-(S)-37
(−)-(S)-39
(77% ee)
(47% ee)
2 2
Preparation of an iBu Mg solution in Et O:
Scheme 5. Configurational assignment of the four sulfoxides of Scheme 4,
which were obtained with 45% ee or more, by sulfoxide-magnesium exchange
reactions with PhMgCl. In three cases, we obtained the dextrorotatory enanti-
Ref.[17] (which, in turn, was based on the procedure by which we had pre-
38
[ ]
2 2
pared iPr Mg in Et O earlier ). The concentration of the resulting solution
[39]
was determined by titration with salicylic aldehyde phenylhydrazone.
[
36]
omer of isobutyl phenyl sulfoxide (43); it is (R)-configured according to ref.
.
Preparation of Heteroaryl Isobutyl Sulfoxides:
Conclusion
General Procedure for the Preparation of Racemic Heteroaryl
Isobutyl Sulfoxides
We synthesized eleven prochiral heterocyclic diaryl sulfoxides.
Ten of these compounds stemmed from metalating a heterocycle
α to the heteroatom and sulfinylating thereafter. Five sulfoxides
iBu
solution of the appropriate diheteroaryl sulfoxide (0.100-0.606 mmol,
.0 equiv.) in THF (1 mL) at room temperature (for further details and
deviations from this procedure: cf. individual descriptions). After complete
conversion, the reaction was quenched by the addition of MeOH (1 mL)
2 2
Mg (0.52-1.18 M solutions in Et O, 0.50-0.55 equiv.) was added to a
1
2 2
underwent a ligand exchange with mixture of iBu Mg and Li -(S)-
BINOLate (9) in 44-77% yield and with 15-88% ee. The highest
enantiopurity was observed for the indole-based sulfoxide (−)-(S)-
and a sat. aqueous solution of NH
The aqueous layer was extracted with t-BuOMe (3 × 2 mL). The combined
organic layers were dried over MgSO and evaporated. The crude product
4
Cl (1 mL). The layers were separated.
39. For reasons unknown, these ligand exchanges were more
structure-dependent and less enantioselective than analogous
reactions of isocyclic diaryl sulfoxides (ref.[16]: up to 100% yield
4
was purified by flash-chromatography on silica[37] (further details: cf.
individual descriptions).
and 97% ee).
General Procedure for the Asymmetric Desymmetrization of
Prochiral Diheteroaryl Sulfoxides with Diisobutylmagnesium
Experimental Section
(1.2 equiv.) and Li
2
-(S)-BINOLate (1.5 equiv; “Treatment A”, cf.
Scheme 4)
Working technique: All reactions were carried out under an atmosphere
of N
Liquids were added with a syringe through a septum. Prior to use THF,
Et O, and diglyme were distilled over sodium or potassium or an alloy of
both under an atmosphere of N . TMPH was distilled over CaH similarly.
2
. Prior to use reaction flasks were dried in vacuo with a heat gun.
At 0°C nBuLi [2.05-2.27
solution of (S)-BINOL (1.5 equiv.) in THF (2 mL). After 10 min stirring was
continued at room temperature for another 10 min. Subsequently, iBu Mg
0.52-1.18 solution in Et O, 1.2 equiv.) was added dropwise. After 10 min
M in hexane, 3.0 equiv.] was added to a precooled
2
2
2
2
(
M
2
Other solvents and reagents were employed as obtained commercially,
i. e. without further purification. Flash-chromatography on silica:
Purification by flash-chromatography was conducted on silica gel 60 (230-
the reaction mixture was cooled to −78°C and a solution of the appropriate
diaryl sulfoxide (0.159-0.279 mmol, 1.0 equiv.) in THF (1.5 mL) was added
during 10 min. After full conversion was achieved (15 min - 2.5 h) the
reaction was quenched by the addition of MeOH (2 mL). The resulting
mixture was warmed to room temperature and diluted with t-BuOMe
4
00 mesh). All eluents were distilled prior to use. Chromatography
conditions are documented in a shorthand form like, e. g. “(c-C 12:AcOEt
a:b, Fr. 10-20)”, which means we eluted with an a:b mixture (v:v) of c-C
6
H
6 12
H
(
5 mL). An aqueous sat. solution of NH
were separated. The aqueous layer was extracted with t-BuOMe (3 ×
mL). The combined organic layers were dried over MgSO and
4
Cl (3 mL) was added. The layers
and AcOEt and that the product was isolated from fractions 10-20. Fraction
and column size were chosen in accordance to the parameters described
by STILL et al.[37] Nuclear magnetic resonance spectra: Spectra were
obtained on a NMR spectrometer (500 MHz, 400 MHz, and 300 MHz for
2
4
evaporated. The crude product was purified by flash-chromatography on
silica[37] (details: cf. individual descriptions) to yield the title compound.
1
13
H; 125 MHz and 100 MHz for C, respectively); referenced internally to
the 1H- and 13C-NMR signals of the solvent [CDCl
7
: 7.26 ppm ( H) and
1
3
General Procedure for the Asymmetric Desymmetrization of
Prochiral Diheteroaryl Sulfoxides with Diisobutylmagnesium
7.10 ppm (13C)]. H-NMR data are reported as follows: chemical shift (δ
1
in ppm), multiplicity (s for singlet; d for doublet; t for triplet; q for quartet; m
for multiplet; m for symmetric multiplet; br for broad signal), coupling
(0.5 equiv.) and Li
2
-(S)-BINOLate (0.63 equiv.; “Treatment B”, cf.
c
Scheme
4)
13
constant(s) (Hz), integral, assignment. C-NMR data are reported in terms
of chemical shift and assignment. Assignments of H NMR and 13C NMR
resonances refer to the IUPAC nomenclature except within substituents
1
At 0°C nBuLi [2.05-2.27
M in hexane, 1.26 equiv.] was added to a
precooled solution of (S)-BINOL (0.63 equiv.) in THF (2 mL). After 10 min
stirring was continued at room temperature for another 10 min.
(
where primed numbers are used) or where explicitly indicated otherwise.
For AB signals the high-field part was named A and the low-field part B.
5
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European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
2
Subsequently, a iBu Mg (0.52-1.18
M
solution in Et
2
O, 0.5 equiv.) was
0.25 mmol, 8%) was obtained as a colorless solid [mp. = 116-118°C
added dropwise. After 10 min the reaction mixture was cooled to −78°C
and a precooled solution (−78°C) of the appropriate diaryl sulfoxide (0.154-
(ref.[40]: 134-136°C)]. 1H NMR (300.1 MHz, CDCl
3
): δ = 7.45 (ddd, J5,6
7.9 Hz, J5,4 = 4.8 Hz, J5,2 = 0.8 Hz, 2H, 2 × 5-H), 8.02 (ddd, J6,5 = 8.0 Hz,
6,2 = 2.2 Hz, J6,4 = 1.7 Hz, 2H, 2 × 6-H), 8.73 (dd, J4,5 = 4.8 Hz, J4.6
1.6 Hz, 2H, 2 × 4-H), 8.84 ppm (dd, J2,6 = 2.2 Hz, J = 0.7 Hz, 2H, 2 × 2-
H). The preceding data are consistent with those in ref.[40].
=
0.435 mmol, 1.0 equiv.) in THF (1.5 mL) was added quickly. After full
J
=
conversion was achieved (10 min – 4.5 h) the reaction was quenched by
the addition of MeOH (2 mL). The resulting mixture was warmed to room
temperature and diluted with t-BuOMe (5 mL). An aqueous sat. solution of
2 5
,
NH
4
Cl (3 mL) was added. The layers were separated. The aqueous layer
Bis(2-furyl) Sulfoxide (23) was prepared following ref.[26] (details:
Supporting Information).
was extracted with t-BuOMe (3 × 2 mL). The combined organic layers were
dried over MgSO
4
and evaporated. The crude product was purified by
flash-chromatography on silica[ (details: cf. individual descriptions) to
37]
Bis(2-thienyl) Sulfoxide (24; known compound[41] which we prepared
yield the title compound.
differently than reported in the literature[41]
)
General Procedure for the Configurational Assignments of the
Enantioenriched Heteroaryl Isobutyl Sulfoxides (−)-34, (−)-37, and (−)-
At −78°C nBuLi (2.43 M in hexane, 6.2 ml, 15 mmol,
O
S
2.0 equiv.) was added dropwise to a precooled
solution of thiophene (1.2 ml, 1.3 g, 15 mmol,
2.0 equiv.) in THF (50 ml). After 30 min at −78°C
S
S
39 by a Sulfoxide-Magnesium Exchange with PhMgCl leading to (+)-
5
(
R)-Isobutyl Phenyl Sulfoxide (43, cf. Scheme 5)
3
4
SOCl
added dropwise. After another 30 min at −78°C the reaction was warmed
to room temperature and quenched after 30 min with aqueous sat. NH Cl-
solution (10 ml). The layers were separated and the aqueous layer was
extracted with t-BuOMe (3 × 20 ml). The combined organic layers were
2
(0.54 ml, 0.89 g, 7.5 mmol) in THF (5 ml) was
At room temp. PhMgCl (1.89
M in THF, 2.5 equiv.) was
added dropwise to a solution of the appropriate heteroaryl
isobutyl sulfoxide (0.102 mmol-0.152 mmol) in THF (1 ml).
After full conversion was achieved (1.5-2.5 h) the reaction
4
was quenched by the addition of aqueous sat. NH
brine (1 ml). The layers were separated and the aqueous layer was
extracted with t-BuOMe (3 × 2 ml). The combined organic layers were dried
4
Cl-solution (1 ml) and
dried over MgSO
4
and evaporated. The residue was purified by flash-
[
37]
chromatography on silica (4 cm, c-C H12:AcOEt 85:15, Fr. 36-60). The
6
title compound [407 mg, 1.90 mmol, 25% (ref.[26]: 0%)] was obtained as a
1
over MgSO
chromatography on silica (3 cm, 20 ml, c-C
4). The product was obtained as a colorless oil. For detailed information
4
and evaporated. The residue was purified by flash-
colorless oil. H NMR (400.1 MHz, CDCl
3
): δ = 7.10 (dd, J
4
,
3
= 5.0 Hz, J4,5
[
37]
= 3.7 Hz, 2 H, 2 × 4-H), 7.54 (dd, J5,4 = 3.8 Hz, J5,3 = 1.4 Hz, 2 H, 2 × 5-H),
7.64 ppm (dd, J3,4 = 5.0 Hz, J3,4 = 1.3 Hz, 2 H, 2 × 3-H). 13C NMR (100.6
6
H12:AcOEt 70:30, Fr. 15-
2
about yields cf. individual descriptions. The optical rotation was assigned
MHz, CDCl
(C-2). The preceding data differ in part form those reported in the
literature.[41] IR (CDCl ): ν
= 3085, 1400, 1340, 1220, 1090, 1045, 1000,
−1. HRMS (ESI): C H OS (M + H
), calculated:
214.96535, found: 214.96539 (∆ = 0.18 ppm). Elemental analysis:
calculated (%) for C OS (214.3 g/mol): C 44.83, H 2.82, S 44.88; found:
C 44.58, H 2.70, S 45.07.
3
): δ = 127.45 (C-4), 130.19 (C-5), 131.89 (C-3), 148.06 ppm
to be dextrorotatory which correlates to the (R)-configured isobutyl phenyl
sulfoxide (43).[36] Under the provisio that this sulfinylation takes place with
̃
3
inversion of the configuration (which is the bottom line of ref. [35]) the
915, 850, 715 cm
+
8
7
3
sulfinylation reagents (−)-34, (−)-37, and (−)-39 are (S)-configured. 1H
NMR (300.1 MHz, CDCl
3
): δ = 1.06 (d, J3‘,2‘ = 6.8 Hz, 3H, 3‘-H
), 2.24 (m , 1H, 2‘-H), 2.47 (dd, J1‘-A,1‘-B = 13.0 Hz,
), 2.81 (dd, J1‘-B,1‘-A = 13.0 Hz, J1‘-B,2‘ = 5.0 Hz, 1H,
), 7.45-7.55 (m, 3H, 3 × Ar-H), 7.59-7.67 ppm (m, 2H, 2 × Ar-H). The
3
), 1.16 (d,
H
8 7
3
J
J
1
3‘‘,2‘ = 6.5 Hz, 3H, 3‘‘-H
1‘-A,2‘ = 9.2 Hz, 1H, 1‘-H
‘-H
3
c
A
B
Bis[(N-phenylsulfonyl)-1H-2-yl-pyrrole] Sulfoxide (25)
[
36]
preceding data are consistent with those reported in the literature. The
ee was determined by chiral HPLC (Chiralcel OD-3, n-heptane/iPrOH
At 0°C nBuLi (2.37 m in hexanes, 1.05 ml,
2.49 mmol, 2.0 equiv.) was added dropwise to
a precooled solution of 2,2,6,6-tetramethyl
piperidine (430 µl, 352 mg, 2.49 mmol,
2.0 equiv.) in THF (3 ml). This solution was
9
r r
5:5, 1 mL/min, λdetector = 209 nm): t (R) = 6.57 min, t (S) = 8.23 min.
ꢇꢈ
Optical rotation: ꢀꢁꢂ
sample had 68% ee); Ref.[ : ꢀꢁꢂ
ꢉ +155.6 (c = 0.57 in EtOH; the respective
ꢃꢄꢅꢆ
36]
ꢇꢈ
3
ꢉ +129.0 [c = 1.0 in CHCl , a sample
ꢃꢄꢅꢆ
of the (R)-enantiomer with 48% ee]. The absolute configuration was
determined by comparing the sense of the optical rotation with literature
data.[36]
stirred for 30 min at 0°C. Then, the solution of LTMP was added dropwise
to a precooled solution of N-phenylsulfonyl pyrrole[28] (517 mg, 2.49 mmol,
2
.0 equiv.) in THF (10 ml) at −78°C. The mixture was stirred for 30 min at
−78°C and then SOCl (90.0 µl, 148 mg, 1.25 mmol) was added. The
resulting mixture was stirred for 30 min, before it was warmed to room
temp. and quenched by the addition of MeOH (2 ml). Aqueous sat. NH Cl-
Bis(2-pyridyl) Sulfide (19) was prepared following ref.[24a] (details:
Supporting Information).
2
4
solution (10 ml) was added. The layers were separated and the aqueous
layer was extracted with t-BuOMe (3 × 10 ml). The combined organic
Bis(2-pyridyl) Sulfoxide (20) was prepared following ref.[24a] (details:
Supporting Information).
layers were dried over MgSO
by flash-chromatography on silica (4 cm, 20 ml, c-C
Fr. 39-63). The title compound (247 mg, 0.536 mmol, 43%) was obtained
as a yellowish solid (mp. = 71-73°C). 1H NMR (400.1 MHz, CDCl
): δ =
.31 (dd, J = 3.8 Hz, J = 3.6 Hz, 1H, 4-H), 6.53 (dd, J5,4 = 3.6 Hz, J
= 1.9 Hz, 1H, 5-H*), 7.40 (dd, J = 3.2 Hz, J = 1.6 Hz, 1H, 3-H*), 7.50-
.54 (m, 2H, 2 × Ar-H), 7.60-7.64 (m, 1H, 1 × Ar-H), 7.97-7.99 ppm (m, 2H,
× Ar-H); *assignments interchangeable. 13C NMR (100.6 MHz, CDCl
):
4
and evaporated. The residue was purified
[
37]
6
H12:AcOEt 60:40,
Bis(3-pyridyl) Sulfoxide (22; known compound[40] which we prepared
differently than reported in the literature[40]
)
3
6
4
,
5
4
,
3
5 3
,
iPrMgCl . LiCl (1.4
M in THF, 4.5 ml, 6.3 mmol, 2.0
O
S
2
3
,
4
3 5
,
equiv.) was added dropwise to a solution of 3-
bromopyridine (0.63 ml, 1.0 g, 6.3 mmol, 2.0 equiv.)
in THF (6 ml) at room temp. After 1 h, the solution
7
2
N
N
3
4
6
5
δ = 113.04 (C-4), 119.74 (C-5*), 126.49 (C-3*), 127.78, 129.61, 134.65,
2
was cooled to −78°C and SOCl (260 µl, 430 mg,
1
2
35.29, 138.01 ppm; *assignments interchangeable. IR (CDCl
3
): νꢊ = 3220,
3.65 mmol) was added dropwise. The reaction was stirred for 30 min at
255, 1710, 1380, 1215, 1180, 1155, 910, 735, 690 cm− . HRMS (CI,
1
−78°C and 30 min at room temp. before it was quenched by the addition
+
MeOH): C20
17 2
H N O
N
5 3
(M + H ), calculated: 461.02996, found: 461.03010
2
of H O (10 ml). The solvents were removed under reduced pressure and
(
∆ = +0.3 ppm).
the residue taken up in CH
2
Cl (20 ml). After filtration of the inorganic salts,
2
the solvent was removed by reduced pressure and the residue was
recrystallized from n-hexane:toluene (1:1, v:v). The title compound (51 mg,
Bis(2-benzo[b]thienyl) Sulfoxide (26) was prepared following ref.[26]
details: Supporting Information).
(
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
Bis[(N-phenylsulfonyl)-1H-indole-2-yl] Sulfoxide (27)
(10 ml) and dried over MgSO . The solvent was evaporated and the
4
residue purified by flash-chromatography on silica[37] (3 cm, 20 ml, c-
At −78°C nBuLi (2.36
M
in hexane, 1.98 ml,
C
6
H
12:AcOEt 85:15, Fr. 10-21). The title compound (218 mg, 0.454 mmol,
4
a
.66 mmol, 2.0 equiv.) was added dropwise to
1
87%) was obtained as a colorless solid (mp. = 72-74°C). H NMR (400.1
precooled solution of N-phenylsulfonyl
MHz, CDCl
3 2 2
, the sample contains a small amount of CH Cl with s at 5.30
indole[ (1.20 g, 4.66 mmol, 2.0 equiv.) in
29]
ppm): δ = 1.67 (s, 18H, 2 × t-Bu), 6.99 (br. s, 2H, 2 × 3-H), 7.28 (ddd, J5,4
THF (25 ml). After 1 h at −78°C SOCl
0.17 ml, 0.28 g, 2.3 mmol) in THF (5 ml) was added dropwise. After
another 30 min at −78°C the reaction was warmed to room temperature
and quenched after 30 min with aqueous sat. NH Cl-solution (10 ml). The
layers were separated and the aqueous layer was extracted with t-BuOMe
3 × 20 ml). The combined organic layers were dried over MgSO and
evaporated. The residue was purified by flash-chromatography on silica
2
=
=
0
7
J
5,6 = 8.1 Hz, J5,7 = 1.0 Hz, 2H, 2 × 5-H*), 7.42 (ddd, J6,5 = J6,7 = 8.5, J6,4
(
1.3 Hz, 2H, 2 × 6-H*), 7.57 (ddd, J4,5 = 8.8 Hz, J4,6 = 1.1 Hz, J4,7 or 4,3
.9 Hz, 2H, 2 × 4-H**), 8.19 ppm (dd, J7,6 = 8.5 Hz, J7,5 = 0.6 Hz, 2H, 2 ×
-H**); *assignments interchangeable; **assignments interchangeable.
=
4
13
C NMR (100.6 MHz, CDCl
13.55 (C-3), 115.76 (C-7), 122.14 (C-4), 123.67 (C-5), 126.57 (C-6),
27.95, 137.68, 142.39, 149.30 ppm. IR (CDCl ): ν = 3325, 2980, 2930,
240, 1740, 1635, 1520, 1470, 1445, 1395, 1370, 1330, 1255, 1215, 1160,
125, 1070, 1055, 1035, 910, 850, 815, 765, 750 cm−1. HRMS (ESI,
3 3 3 3 3
): δ = 28.12 (C(CH ) ), 86.25 (C(CH ) ),
(
4
1
1
2
1
[
37]
3
̃
6
(4 cm, c-C H12:AcOEt 75:25, Fr. 18-37). The title compound (975 mg,
1
1.74 mmol, 75%) was obtained as a colorless solid (mp. = 174-176°C). H
NMR (400.1 MHz, CDCl
1
=
3
, the sample contains a trace of water with s at
.56 ppm): δ = 7.10 (d, J3,4 = 0.8 Hz, 2H, 2 × 3-H), 7.30 (ddd, J = 8.1 Hz, J
7.3 Hz, J = 0.9 Hz, 2H, 2 × 6-H), 7.40-7.47 (m, 6H, 6 × Ar-H), 7.51-7.56
+
MeOH): C26
28
H O
5
SN
2
SNa (M + Na ), calculated: 503.16166, found:
503.16110 (∆ = −1.1 ppm).
(
m, 4H, 4 × Ar-H), 8.14 ppm (ddd, J = 8.5 Hz, J = 1.6 Hz, J = 0.8 Hz, 2H,
Bis[(N-methoxymethyl-1H-benzoimidazole-2-yl)] Sulfoxide (30)
4
1
1
1
-H). 13C NMR (100.6 MHz, CDCl
22.74, 124.47 (C-4), 127.23, 127.54, 128.38, 129.44, 134.50, 137.52,
3
): δ = 114.49 (C-6), 116.12 (C-3),
At room temp. TMPMgCl . LiCl[27] (0.6
M in
37.94, 142.41 ppm. IR (CDCl
3
): ν
ν
̃
ꢊ
= 3355, 2930, 1450, 1375, 1230,
175, 1150, 1125, 1095, 1065, 910, 810, 730, 685, 665 cm 1. HRMS (CI,
−
THF, 3.70 ml, 2.22 mmol, 2.0 equiv.) was
added dropwise to a solution of N-MOM
benzoimidazole[32] (360 mg, 2.22 mmol,
+
MeOH): C28
21 2
H N O
5
S
3
(M + H ), calculated: 561.06126, found: 561.06120
(
(
4
∆ = −0.1 ppm). Elemental analysis: calculated (%) for C28
560.7 g/mol): C 59.98, H 3.60, N 5.00, S 17.16; found: C 60.01, H 3.60, N
.91, S 17.17.
20 2 5 3
H N O S
2
.0 equiv.) in THF (5 ml). After 1.5 h, the
solution was cooled to −78°C and SOCl
80.0 µl, 132 mg, 1.11 mmol) in THF (2 ml) was added. After 15 min, the
solution was warmed to room temp. and stirred for 45 min. The reaction
was quenched by the addition of MeOH (1 ml) and aqueous sat. NH Cl-
2
(
Bis[(N-methoxymethyl)-1H-indole-2-yl] Sulfoxide (28)
4
solution (5 ml). The layers were separated and the aqueous layer was
extracted with t-BuOMe (3 × 5 ml). The combined organic layers were dried
At −30°C nBuLi (2.37
M in hexane, 3.82 ml,
9.05 mmol, 2.0 equiv.) was added dropwise
[
30]
over MgSO
chromatography on silica (4 cm, 20 ml, c-C
4
and evaporated. The residue was purified by flash-
to a precooled solution of N-MOM-indole
[
37]
6
H12:AcOEt 60:40, Fr. 18-33).
(
1.46 g, 9.06 mmol, 2.0 equiv.) in THF
30 ml). After 1 h, SO(OMe) (410 µl, 498 mg,
.53 mmol) was added. After 10 min, the
reaction was warmed to room temp., and after another 30 min, the reaction
was quenched by the addition of MeOH (5 ml) and aqueous sat. NH Cl-
The title compound (129 mg, 0.348 mmol, 31%) was obtained as a
(
4
2
1
colorless solid (mp. = 90-91°C). H NMR (400.1 MHz, CDCl
3
): δ = 3.33 (s,
= 6.03, JAB = 10.9 Hz, 4H, 2 × CH ),
, 4H, 2 × 5-H and 2 × 6-H), 7.59 (ddd, J4,5 = 8.2 Hz, J4,6 = 1.2 Hz,
4,7 = 0.6 Hz, 2H, 2 × 4-H*), 7.81 ppm (ddd, J7,6 = 8.1 Hz, J7,5 = 1.3 Hz, J7,4
6
H, 2 × CH
3
), AB signal (δ
A
= 5.85, δ
B
2
7.38 (m
c
4
J
=
solution (15 ml). The layers were separated and the aqueous layer was
extracted with t-BuOMe (3 × 20 ml). The combined organic layers were
. The solvent was evaporated and the residue purified
by flash-chromatography on silica[37] (5 cm, 20 ml, c-C
13
0.7 Hz, 2H, 2 × 7-H); *assignments interchangeable. C NMR (100.6
): δ = 56.73 (CH ), 75.81 (CH ), 111.71 (C-4*), 121.45 (C-7*),
124.14, 125.86 (C-5 and C-6), 136.21, 142.46, 150.24 ppm (C-2, C-4a and
C-8a); *assignments interchangeable. IR (CDCl ): ν = 3400, 3220, 2935,
1700, 1625, 1485, 1455, 1365, 1290, 1220, 1195, 1165, 1120, 1090, 1070,
015, 915, 745, 690 cm−1. HRMS (ESI, MeOH): C18 S (M + H+),
calculated: 371.11779, found: 371.11780 (∆ = 0.0 ppm).
MHz, CDCl
3
3
2
dried over MgSO
4
6
H12:AcOEt 85:15,
3
̃
Fr. 67-105). The title compound (1.12 g, 3.04 mmol, 67%) was obtained
as a colorless solid (mp. = 50-52°C). 1H NMR (500.4 MHz, CDCl
): δ =
= 5.70, JAB = 11.0 Hz, 4H,
), 7.03 (d, J3,4 = 0.6 Hz, 2H, 2 × 3-H), 7.22 (ddd, J6,7 = 8.0 Hz, J6,5
7.1 Hz, J6,4 = 1.0 Hz, 2H, 2 × 6-H), 7.37 (ddd, J5,4 = 8.3 Hz, J5,6 = 7.1 Hz,
5,7 = 1.1 Hz, 2H, 2 × 5-H), 7.51 (dd, J4,5 = 8.4 Hz, J4,3 or 4,6 = 0.7 Hz, 2H, 2
4-H), 7.66 ppm (dd, J7,6 = 8.9 Hz, J7,5 = 0.8 Hz, 2H, 2 × 7-H). 13C NMR
125.8 MHz, CDCl ): δ = 56.08 (CH ), 75.17 (CH ), 109.03 (C-3), 110.85
C-4), 121.63 (C-6), 122.30 (C-7), 125.24 (C-5), 126.65, 137.08, 139.62
): ν = 3060, 2995, 2940, 2825, 2895, 2245, 1610, 1505,
470, 1445, 1400, 1345, 1325, 1305, 1230, 1160, 1145, 1100, 1085, 1060,
040, 965, 915, 805, 740 cm−1. HRMS (CI, MeOH): C20 S (M + H+),
3
1
19 4 3
H N O
3
2
=
.19 (s, 6H, 2 × CH
3 A B
), AB signal (δ = 5.50, δ
× CH
2
J
×
(
(
Bis[(N-phenylsulfonyl)-1H-benzoimidazole-2-yl] Sulfoxide (31)
At 0°C nBuLi (2.36 in hexane, 1.60 ml,
3
3
2
M
3.70 mmol, 2.0 equiv.) was added dropwise
to a precooled solution of 2,2,6,6-tetramethyl
piperidine (0.66 ml, 0.55 g, 3.9 mmol,
ppm. IR (CDCl
3
̃
1
1
21 3 2
H O N
2.1 equiv.) in THF (3 ml). This solution was
calculated: 369.12729, found: 369.12760 (∆ = −0.8 ppm).
stirred for 30 min at 0°C. Then, the solution
of LTMP was added dropwise to a precooled solution of N-phenylsulfonyl
benzoimidazole[33] (955 mg, 3.70 mmol, 2.0 equiv.), in THF (10 ml) at
Bis[(N-tert-butoxycarbonyl)-1H-indole-2-yl] Sulfoxide (29)
−
2
78°C. After 1 h SOCl (130 µl, 220 mg, 1.85 mmol) in THF (2 ml) was
At −78°C tBuli (1.72
M in hexane, 610 µl,
added. After 30 min, the solution was warmed to room temp. and stirred
for 1 h The reaction was quenched by the addition of MeOH (1 ml) and
aqueous sat. NH
aqueous layer was extracted with t-BuOMe (3 × 10 ml). The combined
organic layers were dried over MgSO
1.04 mmol, 2.0 equiv.) was added dropwise
[
31]
to a precooled solution of N-Boc indole
4
Cl-solution (5 ml). The layers were separated and the
(
227 mg, 1.04 mmol, 2.0 equiv.) in THF
5 ml). After 1 h SOCl (40 µl, 62 mg,
.52 mmol, 1.0 equiv.) was added. After
0 min, the reaction was warmed to room temp. and after another 30 min,
the reaction was quenched by the addition of MeOH (2 ml) and H O (5 ml).
(
0
2
4
and evaporated. The residue was
[37]
6
purified by flash-chromatography on silica (4 cm, 20 ml, c-C H12:AcOEt
3
60:40, Fr. 30-51). The title compound (229 mg, 0.407 mmol, 22%) was
2
1
obtained as a colorless solid (mp. = 179-180°C). H NMR (400.1 MHz,
CDCl , the sample contains a trace of AcOEt): δ = 7.39 (ddd, J = J = 7.5
3
The layers were separated and the aqueous layer was extracted with t-
BuOMe (3 × 5 ml). The combined organic layers were washed with brine
3
3
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
4
Hz, J = 1.1 Hz, 2H, 2 × 5-H*), 7.46-7.51 (m, 6H, 6 × Ar-H, contains 2 × 6-
the Asymmetric Desymmetrization of Prochiral Diheteroaryl Sulfoxides
with Diisobutylmagnesium (1.2 equiv.) and Li -(S)-BINOLate (1.5 equiv.) –
2
Treatment A which resulted in an instantaneous decomposition of the
reaction mixture or the General Procedure for the Asymmetric
3
3
4
4
H*), 7.61 (dddd, J = J = 7.5 Hz, J = J = 1.2 Hz, 2H, 2 × Hpara of SO
2
Ph),
.75 (d, J = 8.2 Hz, 2H, 2 × 4-H**), 7.90 (dd, J = 8.3 Hz, J = 0.8 Hz, 2H,
7-H**), 8.16-8.18 ppm (m, 4H, Ar-H); *assignments
3
4
7
2
×
4 ×
13
interchangeable; **assignments interchangeable. C NMR (100.6 MHz,
CDCl ): δ = 113.04 (C-7*), 122.47 (C-4*), 125.61 (C-5**), 127.38 (C-6**),
28.09, 129.79, 133.29, 135.32, 136.87, 142.24, 153.06 ppm;
assignments interchangeable; **assignments interchangeable. IR
Desymmetrization
of
Prochiral
Diheteroaryl
Sulfoxides
with
3
2
Diisobutylmagnesium (0.5 equiv.) and Li -(S)-BINOLate (0.63 equiv.) -
1
*
Treatment B using bis(2-thienyl) sulfoxide (34.1 mg, 0.154 mmol) [which
delivered (−)-35 (18.6 mg, 99.0 µmol, 64%, 52% ee) after 20 min as a
1
(
1
CDCl
3
): ν
̃
= 3405, 1755, 1715, 1640, 1475, 1390, 1380, 1215, 1195, 1170,
colorless oil]. H NMR (400.1 MHz, CDCl
3
): δ = 1.08 (d, J3’,2’ = 6.8, 3 H, 3’-
125, 1115, 1090, 1050, 1035, 1020, 910, 740, 685 cm−1. HRMS (CI,
H*), 1.11 (d, J3’’,2’ = 6.6, 3 H, 3’’-H*), 2.08-2.22 (m, 1 H, 2’-H), AB signal (δ
= 2.71, δ = 3.12, JAB = 12.8, A part additionally split by d, J1’-A,2’ = 2.1, 1
H, 1’-H ; B part additionally split by d, J1’-B,2’ = 1.4, 1 H, 1’-H ), 7.11 (dd,
4,3 = 5.0, J4,5 = 3.7, 1 H, 4-H), 7.48 (dd, J5,4 = 3.7, J5,3 = 1.1, 1 H, 5-H),
A
+
19 4
MeOH): C26H N O
5
S
3
(M + H ), calculated: 563.05176, found: 563.05120
B
(
(
9
∆ = −1.0 ppm). Elemental analysis: calculated (%) for C26
562.6 g/mol): C 55.50, H 3.24, N 9.96, S 17.10; found: C 55.38, H 3.22, N
.97, S 16.74.
18 4
H N O
5
S
3
A
B
J
7.64 ppm (dd,
interchangeable. C NMR (100.6 MHz, CDCl
J
3,4
=
5.0,
J
3,5
=
1.2,
1
H, 5-H); *assignments
1
3
3
): δ = 21.80 (C-3’’*), 22.66
(
C-3’*), 24.50 (C-2’), 67.90(C-1’), 127.39 (C-4), 129.66 (C-5), 130.93 (C-
), 146.60 ppm (C-2). IR (CDCl ): ν̃ = 3950, 3815, 3670, 3465, 3075, 2960,
3
(
−)-(S)-2-Furyl Isobutyl Sulfoxide (34)
The racemic synthesis followed the General
3
2
1
1
930, 2900, 2875, 2735, 2625, 2400, 2235, 2075, 1815, 1735, 1630, 1595,
555, 1505, 1465, 1405, 1385, 1370, 1270, 1225, 1170, 1110, 1090, 1075,
Procedure for the Preparation of Racemic Heteroaryl
Isobutyl Sulfoxides using di(2-furyl) sulfoxide (50.3 mg,
040, 1000, 945, 920, 850, 815, 730 cm−1. HRMS (CI, MeOH): C
8 2
H13OS
+
(M + H ), calculated: 189.04078, found: 189.04050 (∆ = −1.5 ppm).
0
.276 mmol) with iBu
mmol, 0.55 equiv.) within 35 min. Flash-chromatography
on silica[37] (3 cm, 20 ml, c-C
12:AcOEt 60:40, Fr. 19-33) delivered rac-34
34.6 mg, 0.201 mmol, 73%) as a colorless oil. The asymmetric
2 2
Mg (0.7 M in Et O, 0.22 ml, 0.15
8 2
Elemental analysis: calculated (%) for C H12OS (188.3 g/mol): C 51.03,
H 6.42, S 34.06; found: C 50.88, H 6.28, S 34.20. Optical rotation:
ꢀ
−
6
H
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢁꢂ ꢆꢉ −176.7, ꢀꢁꢂ
ꢉ −84.1, ꢀꢁꢂ ꢆꢉ −43.1, ꢀꢁꢂ
ꢉ −37.1, ꢀꢁꢂ
ꢉ
ꢋꢌꢃ
ꢍꢋꢌꢆ
ꢃꢍꢌ
ꢃꢎꢄꢆ
ꢃꢄꢅꢆ
(
33.8 (c = 0.55 in EtOH). The ee was determined by chiral HPLC
(1)
synthesis was accomplished following either the General Procedure for
the Asymmetric Desymmetrization of Prochiral Diheteroaryl Sulfoxides
with Diisobutylmagnesium (1.2 equiv.) and Li -(S)-BINOLate (1.5 equiv.) –
2
(Chiralpak AD-3, n-heptane/iPrOH 90:10, 1 mL/min, λdetector = 234 nm): t
r
=
16.93 min, t
r
(2) = 18.31 min.
Treatment A using bis(2-furyl) sulfoxide (50.2 mg, 0.276 mmol) [which
delivered rac-34 (39.1 mg, 0.227 mmol, 82%, <1% ee = racemic) after
(−)-(S)-2-Benzo[b]thienyl Isobutyl Sulfoxide (37)
3
0 min as a colorless oil] or the General Procedure for the Asymmetric
Desymmetrization of Prochiral Diheteroaryl Sulfoxides with
Diisobutylmagnesium (0.5 equiv.) and Li -(S)-BINOLate (0.63 equiv.) -
Treatment B using bis(2-furyl) sulfoxide (79.2 mg, 0.435 mmol) [which
delivered (−)-(S)-34 (34.5 mg, 0.200 mmol, 46%, 45% ee) after 30 min as
The racemic synthesis followed the General
Procedure for the Preparation of Racemic
Heteroaryl Isobutyl Sulfoxides using bis(2-
benzo[b]thienyl) sulfoxide (93.0 mg, 0.296 mmol)
2
a colorless oil]. 1H NMR (400.1 MHz, CDCl
H, 3‘-H), 1.10 (d, J3‘‘,2‘ = 2.7 Hz, 3H, 3‘‘-H), 2.11 (m
1‘-A,1‘-B = 12.8 Hz, J1‘-A,2‘ = 8.4 Hz, 1H, 1‘-H ), 3.26 (dd, J1‘-B,1‘-A = 12.9 Hz,
1‘-B,2‘ = 5.9 Hz, 1H, 1‘-H ), 6.51 (dd, J4,5 = 3.6 Hz, J4,3 = 2.0 Hz, 1H, 4-H),
.94 (dd, J5,4 = 3.4 Hz, 1H, 5-H*), 7.64 ppm (dd, J3,4 = 2.1 Hz, J3,5 = 1.1
): δ = 1.08 (d, J3‘,2‘ = 2.2 Hz,
with iBu
0.55 equiv.) within 35 min. Flash-chromatography
on silica[37] (3 cm, 20 ml, c-C
12:AcOEt 60:40, Fr. 19-33) delivered rac-37
(38.3 mg, 0.161 mmol, 54%) as a colorless solid (mp. = 51-53°C). The
asymmetric synthesis was accomplished following either the General
Procedure for the Asymmetric Desymmetrization of Prochiral Diheteroaryl
3
2 2
Mg (0.85 M in Et O, 0.19 ml, 0.16 mmol,
3
J
J
c
, 1H, 2‘-H), 2.83 (dd,
A
6
H
B
6
13
Hz, 1H, 3-H*); *assignments interchangeable. C NMR (100.6 MHz,
CDCl ): δ = 21.71 (C-3‘‘), 22.81 (C-3‘), 24.14 (C-2‘), 61.58 (C-1‘), 111.41
C-4), 116.07 (C-3*), 146.85 (C-5*), 151.95 ppm (C-2); *assignments
interchangeable. IR (CDCl ): ν = 3835, 2960, 2930, 2875, 2425, 2065,
3
Sulfoxides with Diisobutylmagnesium (1.2 equiv.) and Li
2
-(S)-BINOLate
(
(1.5 equiv.)
–
Treatment A[42] using di(2-benzo[b]thienyl) sulfoxide
3
̃
(50.0 mg, 0.159 mmol) [which delivered (−)-(S)-37 (24.3 mg, 0.102 mmol,
64%, 52% ee) after 15 min as a colorless solid (mp. = 51-53°C)] or the
General Procedure for the Asymmetric Desymmetrization of Prochiral
Diheteroaryl Sulfoxides with Diisobutylmagnesium (0.5 equiv.) and Li -(S)-
2
BINOLate (0.63 equiv.) - Treatment B[42] using di(2-benzo[b]thienyl)
sulfoxide (50.0 mg, 0.159 mmol) [which delivered (−)-(S)-37 (29.1 mg,
1
9
1
−
640, 1555, 1465, 1405, 1385, 1370, 1220, 1170, 1130, 1075, 1035, 1010,
10, 865, 760 cm−1. HRMS (CI, NH
Cl): C
H
13SO (M + H ), calculated:
+
4
8
ꢇꢈ
73.06363, found: 173.06360 (∆ = 0.2 ppm). Optical rotation: ꢀꢁꢂꢃꢄꢅꢆ
ꢉ
39.3 (c = 0.40 in CHCl
3
; a sample with 45% ee was used). The ee was
determined by chiral HPLC (Chiralcel OD-H, n-heptane/EtOH 97:3, 1
mL/min, λdetector = 229 nm): t (R) = 15.15 min, t (S) = 16.79 min. The (S)-
r
r
0.122 mmol, 77%, 47% ee) after 10 min as a colorless solid (mp. = 51-
1
configuration was assigned following the General Procedure for the
Configurational Assignments of the Enantioenriched Heteroaryl Isobutyl
Sulfoxides by a Sulfoxide-Magnesium Exchange with PhMgCl using (−)-
53°C)]. H NMR (400.1 MHz, CDCl
3
): δ = 1.11 (d, J3’,2’ = 6.7 Hz, 3H, 3’-H
3
),
1.14 (d, J3’’,2’ = 6.7 Hz, 3H, 3’’-H
2.78, δ
Hz, 1H, 1’-H
(m , 2H, 2 × Ar-H), 7.71 (d, J3,4 = 0.7 Hz, 1H, 3-H), 7.80-7.91 ppm (m, 2H,
2 × Ar-H). 13C NMR (100.6 MHz, CDCl
): δ = 21.88 (C-3’’), 22.69 (C-3’),
4.48 (C-2’), 67.53 (C-1’), 122.94, 124.93, 125.25, 126.27, 126.33 (C-3),
38.34, 141.35, 147.34 ppm. IR (CDCl ): ν νꢊ = 3910, 3475, 3060, 2960,
3
), 2.13-2.27 (m, 1H, 2’-H), AB signal (δ
A
=
B
= 3.16, JA,B = 12.8 Hz, A part additionally split by d, J1’-A,2’ = 8.3
, B part additionally split by d, J1’-B,2’ = 5.8 Hz, 1H, 1’-H ), 7.43
(
2-furyl) isobutyl sulfoxide (a sample with 45% ee, 20.6 mg, 0.120 mmol)
and PhMgCl (1.89 in THF, 0.16 ml, 0.30 mmol, 2.5 equiv.) which
delivered (R)-(+)-43 (6.6 mg, 36 µmol, 30%, 45% ee) as a colorless oil.
A
B
M
c
3
2
1
3
̃
(−)-Isobutyl 2-Thienyl Sulfoxide (35)
2930, 2895, 2870, 1635, 1595, 1505, 1460, 1425, 1390, 1385, 1370, 1325,
1
cm
300, 1245, 1170, 1155, 1110, 1075, 1040, 975, 865, 840, 750, 725, 705
The racemic synthesis followed the General Procedure
for the Preparation of Racemic Heteroaryl Isobutyl
Sulfoxides using bis(2-thienyl) sulfoxide (130 mg,
−1
+
. 2
HRMS (CI, MeOH): C12H15OS (M + H ), calculated: 239.05643,
found: 239.05680 (∆ = −1.5 ppm). Elemental analysis: calculated (%) for
C H14OS (238.4 g/mol): C 60.46, H 5.92, S 26.90; found: C 60.55, H 5.78,
12 2
S 27.23. Optical rotation: ꢀꢁꢂ ꢆꢉ −281.3, ꢀꢁꢂ
0
.606 mmol) with iBu
mmol, 0.55 equiv.) within 30 min. Flash-chromatography
on silica[37] (3 cm, 20 ml, c-C
12:AcOEt 80:20, Fr. 43-50) delivered rac-35
64.2 mg, 0.341 mmol, 56%) as a colorless oil. The asymmetric
2 2
Mg (0.85 M in Et O, 0.39 ml, 0.33
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢉ −124.0, ꢀꢁꢂ ꢆꢉ
ꢃꢍꢌ
ꢋꢌꢃ
ꢍꢋꢌꢆ
ꢇꢈ
ꢇꢈ
−59.8, ꢀꢁꢂ
2% ee was taken). The ee was determined by chiral HPLC (Chiralcel
AD-H, n-heptane/iPrOH 90:10, 1 mL/min, λdetector = 220 nm): t (R) = 12.44
min, t (S) = 14.78 min. The (S)-configuration was assigned following the
ꢃꢎꢄꢆ ꢉ −51.4, ꢀꢁꢂꢃꢄꢅꢆ ꢉ −46.8 (c = 0.63 in EtOH, a sample with
6
H
5
(
r
synthesis was accomplished following either the General Procedure for
r
8
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701309
FULL PAPER
General Procedure for the Configurational Assignments of the
Enantioenriched Heteroaryl Isobutyl Sulfoxides by a Sulfoxide-Magnesium
Exchange with PhMgCl using (−)-2-benzo[b]thienyl isobutyl sulfoxide (a
sample with 47% ee, 24.3 mg, 0.102 mmol) and PhMgCl (1.89 m in THF,
µmol, 0.59 equiv.) within 30 min. Flash-chromatography on silica[37] (2 cm,
20 ml, c-C H12:AcOEt 70:30, Fr. 10-26) delivered rac-39 (9.6 mg, 36 µmol,
6
36%) as a colorless oil. The asymmetric synthesis was accomplished
following either the General Procedure for the Asymmetric
0
8
.14 ml, 0.26 mmol, 2.5 equiv.) which delivered (R)-(+)-43 (15.0 mg,
2.0 µmol, 80%, 40% ee) as a colorless oil.
Desymmetrization
Diisobutylmagnesium (1.2 equiv.) and Li
Treatment A using bis(N-methoxymethyl-indole-2-yl) sulfoxide (90.9 mg,
.247 mmol) [which delivered (−)-(S)-39 (47.1 mg, 0.178 mmol, 72%, 73%
of
Prochiral
Diheteroaryl
Sulfoxides
with
2
-(S)-BINOLate (1.5 equiv.) –
0
(+)-Isobutyl (N-phenylsulfonyl-indole-2-yl) Sulfoxide (38)
ee) after 1 h as a colorless oil] or the General Procedure for the
Asymmetric Desymmetrization of Prochiral Diheteroaryl Sulfoxides with
The racemic synthesis followed the General
Procedure for the Preparation of Racemic
iBu Heteroaryl Isobutyl Sulfoxides using bis(N-
O
PhO S
2
Diisobutylmagnesium (0.5 equiv.) and Li -(S)-BINOLate (0.63 equiv.) -
2
N
S
Treatment B using bis(N-methoxymethyl-indole-2-yl) sulfoxide (106 mg,
7
0
.288 mmol) [which delivered (−)-(S)-39 (54.0 mg, 0.203 mmol, 71%, 88%
6
3
phenylsulfonyl-indole-2-yl) sulfoxide (81.0 mg,
1
ee) after 15 min as a colorless oil]. H NMR (400.1 MHz, CDCl
3
): δ = 1.11
), 2.07-2.21
= 3.28, JAB = 12.8 Hz, A part
; B part additionally split by
), 3.37 (s, 3H, O−CH ), AB signal (δ = 5.66,
= 5.86, JAB = 10.9 Hz, 2H, N−CH ), 7.05 (d, J3,4 = 0.8 Hz, 1H, 3-H), 7.21
ddd, J = 8.0 Hz, J = 7.0 Hz, J = 0.9 Hz, 1H, 6-H), 7.36 (ddd, J
= 7.1 Hz, J = 1.2 Hz, 1H, 5-H), 7.52 (ddd, J4,5 = 8.4 Hz, J4,6
= 0.9 Hz, 1H, 4-H), 7.66 ppm (ddd, J = 8.0 Hz, J = J
1.0 Hz, 1H, 7-H). 13C NMR (100.6 MHz, CDCl
): δ = 21.85 (C-3‘‘), 22.71
), 64.65 (C-1‘), 74.81 (N−CH ), 107.26
C-3), 110.33 (C-5), 121.54 (C-6), 122.19 (C-7), 124.99 (C-4), 126.83,
2 2
0.144 mmol) with iBu Mg (0.52 M in Et O, 0.14 ml,
5
4
(
(
d, J3‘,2‘ = 6.7 Hz, 3H, 3‘-H
m, 1H, 2‘-H), AB signal (δ
3
), 1.12 (d, J3‘‘,2‘ = 6.7 Hz, 3H, 3‘‘-H
3
7
2
µmol, 0.50 equiv.) within 30 min. Flash-
= 2.98, δ
B
[
37]
A
6
chromatography on silica (2 cm, 20 ml, c-C H12:AcOEt 80:20, Fr. 13-21)
additionally split by d, J1’-A,2’ = 8.2 Hz, 1H, 1’-H
d, J1’-B,2’ = 5.9 Hz, 1H, 1’-H
δ
(
8
=
=
(
(
A
delivered rac-38 (20 mg, 56 µmol, 39%) as a colorless oil. The
asymmetric synthesis was accomplished following either the General
Procedure for the Asymmetric Desymmetrization of Prochiral Diheteroaryl
B
3
A
B
2
6
,
7
6
,
5
6
,
4
5 4
, =
Sulfoxides with Diisobutylmagnesium (1.2 equiv.) and Li
1.5 equiv.) Treatment using bis(N-phenylsulfonyl-indole-2-yl)
sulfoxide (97.3 mg, 0.174 mmol) [which delivered (+)-38 (27.6 mg,
6.4 µmol, 44%, 15% ee) after 2.5 h as a colorless oil] or the General
Procedure for the Asymmetric Desymmetrization of Prochiral Diheteroaryl
Sulfoxides with Diisobutylmagnesium (0.5 equiv.) and Li -(S)-BINOLate
0.63 equiv.) Treatment using bis(N-phenylsulfonyl-indole-2-yl)
sulfoxide (105 mg, 0.187 mmol) [which delivered only a trace amount of
2
-(S)-BINOLate
.3 Hz, J
5
,
6
5 7
,
(
-
A
1.7 Hz, J
4
,
3
7
,
6
7
,
5
7 4
,
3
7
C-3‘), 24.59 (C-2‘), 56.27 (O−CH
3
2
2
1
2
7
2
38.08, 139.53 (C-2, C-4a, and C-7a) ppm. IR (CDCl
3
): ν̃ = 3175, 2960,
(
-
B
925, 2870, 2855, 1720, 1615, 1465, 1345, 1310, 1225, 1185, 1130, 1015,
˗
1
14 2
C H20NO S (M +
H+), calculated:
45 cm . HRMS (CI, MeOH):
3
1
2
1
8]. 1H NMR (400.1 MHz, CDCl
.28 (d, J3‘‘,2‘ = 6.7 Hz, 3H, 3‘‘-H ), 2.44-2.53 (m, 1H, 2‘-H), AB signal (δ
.88, δ
3
): δ = 1.12 (d, J3‘,2‘ = 6.7 Hz, 3H, 3‘-H
3
),
=
20
66.12148, found: 266.12170 (∆ = 0.8 ppm). Optical rotation:[α] =
365
3
A
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢇꢈ
ꢀꢁꢂ = −808.3, ꢀꢁꢂ
ꢉ −332.1, ꢀꢁꢂ ꢆꢉ −151.3, ꢀꢁꢂ
ꢉ −126.7,
ꢋꢌꢃꢆ
ꢍꢋꢌꢆ
ꢃꢍꢌ
ꢃꢎꢄꢆ
B
= 3.42, JAB = 12.7 Hz, A part additionally split by d, J1’-A,2’ = 4.3 Hz,
; B part additionally split by d, J1’-B,2’ = 9.9 Hz, 1H, 1’-H ), 7.29
ꢇꢈ
ꢀꢁꢂ
ꢉ−121.3 (c = 0.24 in EtOH; a sample with 88% ee was used). The
ꢃꢄꢅꢆ
H, 1’-H
A
B
3
3
4
ee was determined by chiral HPLC (Chiralcel OD-H, n-heptane/iPrOH
0:10, 1 mL/min, λdetector = 250 nm): t (R) = 19.54 min, t (S) = 22.70 min.
(
ddd, J = 7.9 Hz, J = 7.3 Hz, J = 1.0 Hz, 1H, 5- or 6-H), 7.34 (d, J = 0.8
9
r
r
Hz, 1H, 3-H), 7.37-7.45 (m, 3H, 3 × Ar-H), 7.52-7.57 (m, 2H, 2 × Ar-H),
The (S)-configuration was assigned following the General Procedure for
the Configurational Assignments of the Enantioenriched Heteroaryl
Isobutyl Sulfoxides by a Sulfoxide-Magnesium Exchange with PhMgCl
using (−)-isobutyl (N-methoxymethyl-indole-2-yl) sulfoxide (a sample with
3
4
4
7
1
3
1
1
1
8
C
(
+
.86-7.90 (m, 2H, 2 × Ar-H), 8.15 (ddd, J = 8.5 Hz, J = 1.8 Hz, J = 0.9 Hz,
H, 4- or 7-H). 13C NMR (100.6 MHz, CDCl
3
): δ = 21.43 (C-3‘‘), 22.90 (C-
‘), 24.64 (C-2‘), 68.46 (C-1‘), 114.07 (C-3), 114.31 (C-4 or -7), 122.01,
24.57 (C-5 or -6), 126.29, 126.99, 129.24, 129.52, 134.60, 137.00,
38.71, 143.38 ppm. IR (CDCl ): ν ν̃ ꢊ = 3430, 2960, 2930, 2870, 1585, 1520,
3
7
0
7
7% ee, 40.4 mg, 0.152 mmol) and PhMgCl (1.89 M in THF, 0.20 ml,
.38 mmol, 2.5 equiv.) which delivered (R)-(+)-43 (21.9 mg, 0.120 mmol,
9%, 68% ee) as a colorless oil.
465, 1445, 1400, 1375, 1340, 1310, 1225. 1175, 1120, 1090, 1080, 1045,
95, 835, 810, 750, 730, 685, 665 cm−1. HRMS (ESI, MeOH):
+
18
H19NO
3
S
2
Na (M + Na ), calculated: 384.07041, found: 384.07090
ꢇꢈ
ꢇꢈ
ꢇꢈ
∆ = 1.3 ppm). Optical rotation: ꢀꢁꢂ
ꢉ +40.1, ꢀꢁꢂ ꢆꢉ +16.5, ꢀꢁꢂ
ꢉ
ꢍꢋꢌꢆ
ꢃꢍꢌ
ꢃꢎꢄꢆ
ꢇꢈ
13.7, ꢀꢁꢂ
ꢉ +11.6 (c = 1.60 in EtOH). The ee was determined by chiral
Acknowledgements
ꢃꢄꢅꢆ
HPLC (Chiralcel AD-H, n-heptane/iPrOH 90:10, 1 mL/min, λdetector = 250
nm): t (−) = 21.86 min, t (+) = 26.66 min.
r
r
The authors thank the Deutsche Forschungsgemeinschaft for
financial support (project BR 881-7).
(−)-(S)-Isobutyl (N-methoxymethyl-indole-2-yl) Sulfoxide (39)
Keywords: BINOL • desymmetrization • dialkylmagnesium rea-
gents • diaryl sulfoxides • enantioselectivity • sulfoxide/magnesi-
um exchange
The racemic synthesis followed the General
Procedure for the Preparation of Racemic
Heteroaryl Isobutyl Sulfoxides using bis(N-
methoxymethyl-indole-2-yl) sulfoxide (37.0 mg,
2 2
0.100 mmol) with iBu Mg (1.18 M in Et O, 50 µl, 59
[
1]
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Arylsulfimides” in Science of Synthesis: Houben-Weyl Methods of
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Stuttgart 2007, 907-948.− b) K.-M. Roy, "Sulfones and Sulfoxides" in
Ullmann's Encyclopedia of Industrial Chemistry, Vol. 34, Wiley-VCH,
Weinheim 2000, 705-720.− c) J. Drabowicz, P. Kiełbasinski, M.
Mikołajczyk, “Synthesis of Sulphoxides” in Sulphones and Sulphoxides
f) G. Hanquet, F. Colobert, S. Lanners, G. Solladié, ARKIVOC 2003, Part
vii, 328-401.− g) C.-C. Wang, H.-C. Huang, D. B. Reitz, Org. Prep.
Proced. Int. 2002, 34, 271-319.
Recent reviews: a) S. Otocka, M. Kwiatkowska, L. Madalińska, P.
Kiełbasiński, Chem. Rev. 2017, 117, 4147-4181.− b) B. M. Trost, M. Rao,
Angew. Chem. 2015, 127, 5112-5130; Angew. Chem. Int. Ed. Engl.
2015, 54, 5026-5043.− c) M. Mellah, A. Voituriez, E. Schulz, Chem.
Rev. 2007, 107, 5133-5209.− d) H. Pellissier,Tetrahedron 2007, 63,
1297-1330.
Reviews: a) Q. Zeng, S. Gao, A. K. Chelashaw, Mini Rev. Org.
Chem. 2013, 10, 198-206.− b) A. Scarso, G. Strukul, “Transition-Metal-
Catalyzed Asymmetric Sulfoxidation in Drug and Natural Product
Synthesis” in Stereoselective Synthesis of Drugs and Natural Products
(Eds.: V. Andrushko, N. Andrushko), John Wiley & Sons, Hoboken, 2013,
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a
magnesium enolate rather than an
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1
9
94 reported deviating and/or faulty NMR data for 24: H NMR (500 MHz,
[18] Synthesizing 5, we experienced no over-reaction giving dialkylsulfoxides
CDCl
protons): δ = 7.08-7.16 (m, 2H, 2 × Ar-H), 7.44 (dd, J = 3.8 Hz, J = 1.3 Hz,
H, Ar-H), 7.55 (dd, J = 3.7 Hz, J = 1.2 Hz, 1H, Ar-H), 7.62 (dd, J = 5.0
Hz, J = 1.2 Hz, 1H, Ar-H), 7.87 ppm (dd, J = 3.0 Hz, J = 1.2 Hz, 1H, Ar-
3
; 5 chemical shifts – integral ratio = 2:1:1:1:1 – for 3 kinds of
7
(Scheme 1). Benzyl pyrid-3-yl sulfoxide and PhMgBr even prefer such
an over-reaction. It delivered diphenyl sulfoxide in 48% yield: a) T. Kawai,
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1
H); 13C NMR (125 MHz, CDCl
; 5 chemical shifts for 4 kinds of C nuclei):
13
3
δ = 128.34, 131.10, 132.26, 144.45, 147.29 ppm.
[
42] The workup procedure for this reaction was modified by washing the
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combined organic layers prior to drying with MgSO
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similar R -value as the product and therefore would have led to mixtures
after flash-chromatography.
4
with an aqueous
2
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[
f
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10
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