Asymmetric Sulfinylations of N-Methylephedrine-Modified Tri- or Tetraalkyl Zincates by Symmetric Diaryl Sulfoxides

Article abstract of DOI:10.1002/ejoc.201701603

Diethylzinc was treated with 1 or 2 equiv. of AlkMgCl or PhMgBr (preferably) or with 1 equiv. of nBuLi (less efficiently) for forming species – plausibly zincates – which were sulfinylated by diaryl sulfoxides to give racemic alkyl aryl sulfoxides in yields reaching 100 %. Dialkylzinc reagents were also activated by treatments with 1 or 2 equiv. of an enantiomerically pure alkylmagnesium β-aminoalkoxide. This worked best when the alkoxide stemmed from a dialkylmagnesium reagent and an equimolar amount of N-methyl-(–)-ephedrine. This second activation mode allowed sulfinylations of what was originally the dialkylzinc reagent with diaryl sulfoxides. This generated alkyl aryl sulfoxides with enantiomeric ratios up to 93:7 in up to 100 % yield.

Full text of DOI:10.1002/ejoc.201701603

A Journal of
Accepted Article
Title: Asymmetric Sulfinylations of N-Methylephedrine-Modified Tri- or
Tetraalkyl Zincates by Symmetric Diaryl Sulfoxides
Authors: Reinhard Brückner and Simon Ruppenthal
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701603
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
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((Keywords for Table of Contents:))
Asymmetric Sulfinylations
((Graphical Abstracts:))
S. Ruppenthal, R. Brückner*
Asymmetric Sulfinylations of N-Methylephedrine-Modified Tri- or
Tetraalkyl Zincates by Symmetric Diaryl Sulfoxides
OH
AlkMgO
Alk2Zn
Alk2Mg
Ph
Ar
(1:1 or
1:2 ratio);
Ph
(1:1 ratio),
THF, rt;
NMe2
NMe2
A
O
S
O
MgO
Ph
Ar
Ar
Alkyl3-4Zn1-2
S
Alk
C
NMe2
B1 or 2
D
1-2
Dialkylmagnesium compounds deprotonate β-aminoalcohols, e. g. N-methyl-(−)-ephedrine. Plausibly, this renders β-aminoalkoxide
analogs of Grignard reagents, e. g. compound A. One or two equivalents of the latter activate dialkylzinc compounds – perhaps as
zincates B1 or B2 – such that their alkyl moiety is sulfinylated by symmetric diaryl sulfoxides C. This provides alkyl aryl sulfoxides D in
up to 100% yield with ee´s reaching the mid-80s.
1
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Asymmetric Sulfinylations of N-Methylephedrine-Modified Tri- or
Tetraalkyl Zincates by Symmetric Diaryl Sulfoxides
Simon Ruppenthal[a] and Reinhard Brückner*[a]
Abstract: Diethylzinc was treated with 1 or 2 equiv. of AlkMgCl or
PhMgBr (preferably) or with 1 equiv. of nBuLi (less efficiently) for
forming species − plausibly zincates – which were sulfinylated by
diaryl sulfoxides to give racemic alkyl aryl sulfoxides in yields reaching
100%. Dialkylzinc reagents were also activated by treatments with 1
dialkylmagnesium reagent and an equimolar amount of N-methyl-(−)-
ephedrine. This second activation mode allowed sulfinylations of what
was originally the dialkylzinc reagent with diaryl sulfoxides. This
generated alkyl aryl sulfoxides with enantiomeric ratios up to 93:7 in
up to 100% yield.
or
2 equiv. of an enantiomerically pure alkylmagnesium β-
aminoalkoxide. This worked best when the alkoxide stemmed from a
the S-atom.[8] The third organozinc sulfinylation of Scheme 1[9] af-
fects the mixed trialkyl zincates nBuEt2Zn⊖ ⊕Li[10] which are more
nucleophilic than alkylzinc halides or dialkylzinc compounds.[6] In
this case the sulfinylating agent was the α-cyanoalkyl phenyl sulf-
oxide 8.[9] It was the first sulfoxide to sulfinylate an organozinc
compound.[9] At 0°C in THF this sulfinylation delivered ethyl phe-
nyl sulfoxide (9a) and butyl phenyl sulfoxide (9b).[9] Both com-
pounds were barely looked at, though.[9] This was because the
focus was on follow-up reactions of the leaving group, that is of
the α-zincated nitrile 10[11] (e. g. by Mander´s reagent, which re-
acted to give the cyano ester 11[9]). The sulfinylating sulfoxides 8
of the respective study[9] were racemic. They must have given the
sulfoxides 9a and b as racemic mixtures accordingly.
In contrast, we prepared alkyl aryl sulfoxides[12] – including ethyl
phenyl sulfoxide (9a) – and alkyl heteroaryl sulfoxides[12c] asym-
metrically: by sulfinylating dialkylmagnesium compounds with
symmetric (!) diaryl[12a-b] or diheteroaryl sulfoxides.[12c] Asymmetry
arose from adding Li2-(S)-BINOLate.[12] Its involvement led to the
transfer of uniquely configured arylsulfinyl groups or heteroaryl-
sulfinyl groups from the respective sulfoxides. This was (1) in spite
of their symmetry and thus (2) by desymmetrizing them[11]). Being
the first reactions of their kind these sulfinylations succeeded in
up to 100% yield with up to 97% ee.[12]
The latter route to sulfoxides, our previous endeavors into asym-
metric synthesis by desymmetrization approaches,[13] and the fea-
sibility of sulfoxide-mediated sulfinylations[9] 8 + nBuEt2Zn⊖ ⊕Li →
9 + 10 (Scheme 1) were an incentive to identify the first asymmet-
ric sulfinylations of alkylzinc compounds with symmetric diaryl
sulfoxides. This intention and our respective results are sketched
at the bottom of Scheme 1: Tri- or tetraalkyl zincate anions juxta-
posed by (S,S)-configured β-amino(magnesioalkoxide) cations 12
picked up arylsulfinyl groups from diaryl sulfoxides 11 with up to
86% ee. Usually this gave sulfoxides 13 with an (S)-configuration.
Literature Sulfinylations of Organozinc Com-
pounds
The S-atom in sulfoxides is pyramidalized which makes unsym-
metric sulfoxides chiral. The respective stereocenter remains sta-
ble unless the compound is heated excessively[1] or stereoran-
domizes by an EVANS-MISLOW rearrangement. Synthesizing sulf-
oxides enantioselectively is possible in many ways.[2] Probably,
the most versatile access is by the enantioselective oxidation of
unsymmetric sulfides.[2] Alternatively, enantiomerically pure sulf-
oxides result from the asymmetric sulfinylation of an organome-
tallic. The latter access was pioneered by the para-toluenesufinyl-
ation of ethylmagnesium iodide by (−)-menthyl (−)-p-toluenesulfi-
nate.[3] Methyl lithium[4] and Gilman cuprates react analogously.[5]
Organozinc compounds[6] tolerate more functional groups than
analogous organomagnesium, -lithium or -copper compounds.
This reflects the lower nucleophilicity of the former compounds.
Accordingly, very few organozinc compounds seem to have been
sulfinylated giving a sulfoxide at all. The only examples of this ap-
proach of which we are aware are summarized in Scheme 1.
According to the top of Scheme 1 tert-adamantylzinc bromide and
the enantiomerically pure sulfurous N-tosylamide 1 gave the sul-
finate 2 with an inversion of configuration at the S-atom.[7] The
second reaction of Scheme 1 – between a picolylzinc chloride and
the sulfinate 5 – demonstrates that sulfinates may sulfinylate or-
ganozinc compounds, too;[8] however, such a possibility was not
explored engaging the sulfinate 2 and adamantylzinc bromide.[7]
The mentioned sulfinylation with the sulfinate 5 led to the sulfoxide
7 (“esomeprazole®“) with complete inversion of configuration at
[a]
M. Sc. Simon Ruppenthal, Prof. Dr. R. Brückner
Institut für Organische Chemie
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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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
amount of lithium 2-(dimethylamino)ethanolate to the Et2Zn(entry
.
2) or by adding 1.0 equiv. BF3 OEt2 to the sulfoxide[15] (entry 3).
O
S O
O
S
N
O
O
Table 1. Towards
a racemic phenylsulfinylation of diethylzinc-containing
BrZnN
Ref.[7]
:
ZnBr
O
S
reagents[a,b] by diphenyl sulfoxide (16).
S
O
O
THF,
Mn
−45°C - −15°C;
O
O
S
RnEt2Znn
(1/n eq.),
Mn
1
2
n
S
RnEt2Zn
NHSO2Ar
OMgBr
Et
+
Bu
S
O
THF, room temp.,
time
nBuMgBr,
+
16
9a
17
THF, −78°C
3
4
Other
sulfoxides
93% (>99% ee)
#
R
n
M
Additive (1.0 eq.) Time Yield 9a
MeO
1
1.5 h
O
N
S
+
no con-
3 h
2
3
0
N
ZnCl
N
H
O
N
OMe
version
Ref.[8]
:
5
5 h
BF3 . OEt2
MeO
Li
8%
PhS(=O)Bu
4
3.5 h
22%
N
Bu
Et
+
S
OZnCl
O
N
H
OMe
5
6
87%
91%
6
7
Me3SiCH2
1
MgCl
MgBr
17%
PhS(=O)iPr
7
18%
Ref.[9]
:
O
O
S
O
S
iPr
CN
CN
20 min
LxZn
S
nBuEt2Zn
Li
Et
Bu
+
+
8
65%
100%
84%
tBu
Ph
Et
THF,
0°C;
9
8
9a
9b
10
(without yield)
(without yield)
10
2 (MgCl)2
[a]The triorganozincates were prepared by mixing ZnEt2 and 1.0 equiv. of an organolithium or
Grignard reagent in THF at room temp. (10 min).− [b]The tetraethyl zincate stemmed from
mixing ZnEt2 and 2.0 equiv. of EtMgCl in THF at room temp. (10 min).
LxZn
O
N
C
O
CN
MeO
CN
MeO
11 (92%
iso-10
The mixed triorganozincate nBuEt2Zn⊖ ⊕Li had been phenylsulfi-
nylated by the (activated) sulfoxide 8 of Scheme 1.[9] This sug-
gested to combine the same zincate with diphenyl sulfoxide (16).
This provided ethyl phenyl sulfoxide (9a) in 22% yield and butyl
phenyl sulfoxide in 8% yield (Table 1, entry 4). Thereupon other
organo diethyl zincates were tested similarly. Therein we replaced
This
work:
Alkyl3Zn
MgO
Ph
NMe2
O
O
S
LxZnn
12a
S
or
Alkyl
+
R
R
R
R
Alkyl4Zn2
MgO
Ph
[16]
Li by MgHal and nBu by Et, Me3SiCH2 , iPr[17], tBu[18], and Ph
11
13
14
NMe2
up to 100%
up to 84% ee
typically (S)
(entries 5-9). At room temp. the respective phenylsulfinylations
were over within 20 min. The homo-zincate Et3Zn⊖ ⊕MgCl ren-
dered ethyl phenyl sulfoxide (9a) in 87% yield (entry 5). The mixed
zincates (Me3SiCH2)Et2Zn⊖ ⊕MgCl (entry 6, 91% yield),
tBuEt2Zn⊖ ⊕MgCl (entry 8, 65% yield), and PhEt2Zn⊖ ⊕MgBr (en-
try 9, quantitative yield) reacted analogously; their phenylsulfinyl-
ations affected the ethyl moiety exclusively. In contrast, the mixed
zincate iPrEt2Zn⊖ ⊕MgCl (entry 7) reacted with the ethyl (→ 18%
9a) and with the isopropyl moiety (→ 17% isopropyl phenyl sul-
foxide). Finally, the tetraethyl zincate Et4Zn2⊖ ⊕(MgCl)2 was phe-
nylsulfinylated; it performed almost as well (→ 84% 9a, entry 10)
as the triethyl zincate Et3Zn⊖ ⊕MgCl (→ 87% 9a, entry 5).
12b
2
THF, typically −78 to −40°C
Scheme 1. Sulfoxide formation from organozinc reagents. The functionalization
of adamantylzinc bromide provided the sulfinate 3, not a sulfoxide (at top). How-
ever, a related sulfinate 5 converted a benzylzinc chloride into the sulfoxide 7
(underneath). Combining both findings suggests that compound 1 would suit as
a linchpin for incorporating two different alkylzinc halides into a single(-
configured) sulfoxide.
Racemic Phenylsulfinylations of “Activated
Diethylzinc”
First we investigated the racemic phenylsulfinylation of Et2Zn-con-
taining organometallics testing diphenyl sulfoxide (16) as the sul-
finylating reagent. It is known that alkylzinc halides and dialkylzinc
reagents are unreactive towards sulfoxides.[14] We verified the lat-
ter fact (Table 1, entry 1) by mixing Et2Zn and 16 in THF at room
temperature (entry 1). No reaction occurred. The same was true
for two related experiments. Employing the same reagents we
tried to activate one of them either by adding a stoichiometric
Asymmetric Arylsulfinylations of “Activated
Diethylzinc”
Having established, inter alia, the suitability of magnesium trior-
ganozincates for undergoing racemic phenylsulfinylations by di-
phenyl sulfoxide (16) (Table 1) we wondered whether changing
their cation moiety MgHal into MgOR* allows to perform such
3
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Table 2. The first asymmetric (“desymmetrizing”[11]) phenylsulfinylations of tri-
ethyl zincates containing enantiopure magnesium β-aminoalkoxide counter-
ions using diphenyl sulfoxide (16) as the sulfinylating agent I: first counterion
variations.
phenyl- or analogous arylsulfinylations still using the symmetric
diphenyl sulfoxide (16) or other symmetric diaryl sulfoxides as
sulfinylating agents. We determined that the OR* moiety of the
envisaged cations MgOR* should originate from homochiral β-
aminoalcohols. This choice was mainly based on the plausibility
of being chelating ligands. Obviously, we could have tested ho-
mochiral glycols – or TADDOLs or BINOLs – with similar hopes.
Focusing instead on β-aminoalcohols was inspired to some extent
by their potential of making diethylzinc additions to aldehydes en-
antioselective.[19] Of course, these additions rely on catalytic
amounts of a β-aminoalcohol while our arylsulfinylations utilize
stoichiometric amounts of the respective β-aminoalkoxides. This
difference is quite basic. Nonetheless, studying triorganozincates
R3Zn⊖ ⊕MgOR* at least formally would concern novel kinds of or-
ganozincates. Whatever they would really be,[20] the potential of
their O- and N-atoms for binding not only to magnesium but also
to zinc appeared likely to define such species spatially precisely.
This might lead to good asymmetric inductions.
a)
MgOR*
Et3Zn
HOR*
17-26
in situ
O
S
O
S
*
THF, −40°C, 20-21.5 h
16
entry
9a
(up to 62% ee)
Yield; ee (configuration)[a]
R*OH
1[b],[23]
70%; 16% ee (+)-(R)
2[b],[24]
3[c]
76%; 57% ee (−)-(S)
93%; 62% ee (−)-(S)
4[c]
66%; 13% ee (+)-(R)
85%; 15% ee (+)-(R)
trace; ee not measured
Table 2 - Table 5 summarize our results. Each experiment began
with preparing a solution of what, we hypothesized, was an enan-
tiomerically pure “zincate”.[20] Its overall composition was
OH
NMe2
5[c]
20
2
⊖
Et3Zn⊖ ⊕MgOR* or REt2Zn⊖ ⊕MgOR* or Et4Zn (⊕MgOR*)2.
Their OR* moiety was a β-aminoalkoxide. The respective amino-
alcohol was dissolved in THF and combined with an Et2O solution
of Et2Mg (Table 2, Table 3, Table 5) or Alkyl2Mg (Table 4) (room
temp., 30 min). This was supposed to give the alkylmagnesium
aminoalkoxide. The latter was carried on to the (surmised) zincate
by treatment with 1.0 or 0.5 equiv. of Et2Zn at room temp.[21]. That
reagent was cooled to typically −40°C.[22] A THF solution of our
benchmark sulfoxide 16 was added dropwise. The respective sul-
finylation was allowed to progress at −40°C overnight. Usually,
this ensured complete conversions.
OH
Me
N
Ph
Ph
6[c],[25]
21
OMe
OH
N
7[c],[26]
98%; 29% ee (−)-(S)
100%; 3% ee (+)-(R)
N
(−)-quinine 22
OMe
OH
N
8[c],[26]
The β-aminoalcohol precursors of our ethylmagnesium β-amino-
alkoxide cation moieties ⊕MgOR* (cf. above) were varied
extensively in rounds 1 (Table 2) and 2 (Table 3) of our study.
Most of them had a history of having been employed as
successful chiral promoters other kinds of organozinc reactions.
The β-aminoalcohols allowing the phenylsulfinylations of Table 2
stemmed from ephedra alkaloids (17[23] and 18[24]), amino acids
(19, 20, and 21[25]) or chinchona alkaloids (22[26] and 23[26]) or
were synthetic materials introduced by Nugent (24[27], 25[28], and
26[28]). The sulfinylations of Table 3 leaned on N-alkylated (−)-
ephedrines (18[24], 27[23], 28[29], 29[30], and 30[29,31]) and N,N-
dialkylated (−)-norephedrines (31[29], 32[29], 33[29], and 34[29]).
The best ee values of the phenylsulfinylations summarized in
Table 2 were due to the cation ⊕MgOR* derived from N-methyl-
(−)-ephedrine (17; entries 2 and 3): adding diphenyl sulfoxide (16)
to the precooled organozincate[20] delivered sulfoxide (−)-(S)-9a in
76% yield with 57% ee (entry 2). The inverse addition mode was
more satisfactory, though (entry 3). It increased both yield (93%)
and enantioselectivity (62% ee). Therefore, the second procedure
was adopted for all remaining arylsulfinylations – with a single ex-
ception, namely the phenylsulfinylation in the presence of the
magnesium alkoxide of N-methyl-(+)-pseudoephedrine (17, entry
1). In Table 2 these reactions proceeded with low to modest en-
antioselectivities (3-29% ee) in good to excellent yields (66-
100%).
N
(+)-quinidine 23
O
N
9[c],[27]
93%; 29% ee (+)-(R)
93%; 7% ee (+)-(R)
OH
24
OH
O
N
10[c],[28]
25
OH
O
N
11[c],[28]
73%; 11% ee (+)-(R)
26
Reagents and conditions: a) Et2Mg (1.0 equiv.), THF, room temp., 30 min; ZnEt2
(1.0 equiv.), 10 min.− [a]Sulfoxide (−)-9a is (S)-configured according to a previous
study.[12b] As a consequence, sulfoxide (+)-9a must be (R)-configured. The configura-
tion of the major enantiomer of all specimens of sulfoxide 9a resulting from the exper-
iments tabulated here was deduced from its migratory aptitude on a Chiralcel OD-3
column in n-heptane/iPrOH 96:4 (cf. Experimental Section): (−)-(S)-9a eluted slower
than (+)-(R)-9a.− [b]A solution of sulfoxide 16 was added dropwise to a solution of
“organozincate” precooled to −40°C; the reaction was quenched with MeOH after TLC
showed complete conversion of the starting material (except for entry 6 where only a
trace amount of starting material was consumed) and worked up with aqueous sat.
NH4Cl-solution and tBuOMe.− [c]We proceeded as in footnote [b] but added the
solution of the “zincate” to a solution of the sulfoxide 16 which had been precooled to
−40°C.
4
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
Table 3. Asymmetric (“desymmetrizing”[11]
)
phenylsulfinylations of triethyl
Table 4. Optimizing the asymmetric (“desymmetrizing”[11]) phenylsulfinylation
of ethyl-containing zincates juxtaposed by an N-methyl-(−)-ephedrine-based
magnesium β-aminoalkoxide counterion using diphenyl sulfoxide (16) as the
sulfinylating agent.
zincates containing enantiopure magnesium β-aminoalkoxide counterions
using diphenyl sulfoxide (16) as the sulfinylating agent II: fine-tuning the
(−)-ephedrine (→ 18 and 27-29) and (−)-norephedrine (→ 30-34) substituents.
Et3Zn
MgO
Ph
OH
2
a)
Et4Zn
MgO
Ph
REt2Zn
MgO
Ph
OH
NR2
NR2
a) or b)
Ph
NMe2
in situ
NMe2
NMe2
or
Ph
18
in situ
35-39
40
18, 27-34
n
O
S
O
O
O
S
S
S
*
THF, −40°C, 20 h
THF, −40°C, 20 h
16
9a
16
(−)-(S)-9a
(up to 69% ee)
(up to 62% ee)
entry
Yield; ee (configuration)[a]
Yield; ee
entry
Organozincate
Solvent
(configuration)[a]
OH
93%; 62% ee
(= Table 2, entry 3)
93%; 62% ee (−)-(S)
(= Table 2; entry 3)
NMe2
1[24]
1
THF
Ph
Ph
18
OH
2
Et2O
45%; 2% ee
no conversion
53%; 2% ee
72%; 63% ee
87%; 31% ee (−)-(S)
N
2[23]
MgO
Et3Zn
27
NMe2
Ph
OH
OH
3
DME
toluene
N
3[29]
Ph
96%; 5% ee (−)-(S)
35
28
4
O
N
4[30]
Ph
29
100%; 20% ee (−)-(S)
O
5[b]
OH
MgO
Ph
(Me3SiCH2)Et2Zn
N
6
7
8
9
89%; 62% ee
66%; 3% ee
69%; 28% ee
49%; 37% ee
NMe2
Ph
5[29,31]
34%; 3% ee (−)-(S)
92%; 5% ee (−)-(S)
62%; 13% ee (+)-(R)
36
30
MgO
Ph
iPrEt2Zn
OH
NMe2
NMe2
NMe2
N
N
6[29]
37
Ph
31
THF
MgO
Ph
tBuEt2Zn
38
OH
7[29]
Ph
MgO
Ph
32
OH
PhEt2Zn
OMe
39
8[29]
34%; 8% ee (+)-(R)
90%; 7% ee (+)-(R)
N
N
2
Ph
Et4Zn
MgO
Ph
33
NMe2
10
86%; 69% ee
OH
40
9[29]
Ph
[a]The predominant configuration of sulfoxide 9a was determined as detailed in foot-
note [a] of Table 2.
[b]2.0 equiv. of the “organozincate” were used.− Reagents and
34
−
[a]The predominant configuration of sulfoxide 9a was determined as detailed in
footnote [a] of Table 2.− Reagents and conditions: a) Et2Mg (1.0 equiv.), THF, room
temp., 30 min; ZnEt2 (1.0 equiv.), 10 min; thereafter we proceeded as described in
footnote [c] of Table 2.
conditions: a) Et2Mg or Alkylnon-transferable,2Mg (1.0 equiv.), THF, room temp., 30 min;
ZnEt2 (1.0 equiv.), 10 min; thereafter we proceeded as described in footnote [c] of
Table 2.− b) Same as a) except for using Et2Mg (2.0 equiv.).
The phenylsulfinylations recorded in Table 4 maintained N-
methylated (−)-ephedrine (18) as the chiral auxiliary but varied the
reaction conditions; the resulting sulfoxide (9a) was always (S)-
configured:
The triethyl zincate of Table 2 which was phenysulfinylated with
the highest enantioselectivity (62% ee) was derived from “N,N-
dimethylated (−)-norephedrine” [= N-monomethylated (−)-ephed-
rine; 18]. This led us to examine the enantiocontrol exerted by
eight other N,N-dialkylated ephedra alkaloids (Table 3). None of
them topped the result of N-methyl-(−)-ephedrine (18, entry 1),
however. On the contrary, low ee’s (5%-31%) resulted. The in-
creased sterical demand at the nitrogen seems to affect enantio-
control adversely − to the point of inverting it from a weak (S)-
(entries 1-6) to a weak (R)-preference (entries 7-9).
1) We moved from THF as the solvent to Et2O, dimethoxyethane
(“DME”) or toluene (entries 2-4). Using Et2O and toluene de-
creased yield (45% or 53%, respectively) and uplifted enantiocon-
trol (2% ee). DME stopped the phenylsulfinylation altogether.
2) We increased the proportion of “Et⊖” in the reaction mixture:
either by using twice as much triethyl zincate 35 (entry 5; → 72%
yield and 63% ee) or by using an equimolar amount of the analo-
gous tetraethyl zincate (40, entry 10; → 86% and 69% ee). The
5
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
second result was tantamount to a small yield decrease (86% in-
stead of 93% in entry 1) and ee increase (69% instead of 62% in
entry 1).
(37-39) were inferior (entries 7-9; → 49-69% yield and 3-37% ee)
to the triethyl zincate 35 (entry 5; → 72% yield and 63% ee), the
Me3SiCH2-modified zincate 36 slightly superior (entry 6; → 89%
yield and 62% ee). However, this left 36 inferior compared to the
tetaethyl zincate 40 (entry 10; → 86% and 69% ee). Accordingly,
we continued our sulfinylations employing only the tri- and the
tetraethyl zincate.
3) Similarly as recorded in Table 1, we compared the
phenylsulfinylation
of
the
triethyl
zincate
35
with
phenylsulfinylations of the mixed alkyl or phenyl diethyl zincates
36-39 (entries 6-9). The latter contained a non-transferable group
which, other than in Table 1 (cf. entry 7 there and entry 7 here),
included the iPr group. The iPr-, tBu-, and Ph-modified zincates
Table 5. Asymmetric (“desymmetrizing”[11]) aryl- rather than phenylsulfinylations of ethyl-containing zincates juxtaposed by an N-methyl-(−)-ephedrine-based
magnesium β-aminoalkoxide counterion using symmetric diaryl rather than diphenyl sulfoxides as sulfinylating agents. The absolute configuration of the resulting
sulfoxides emerged from their levorotation; it correlates with their stereostructure as previously established.[12b]
2
Et4Zn
MgO
Ph
Et3Zn
MgO
Ph
OH
a) or b)
NMe2
NMe2
NMe2
or
Ph
in situ
35
40
n
18
O
S
O
S
Aryl
Aryl
Aryl
THF, temp., 20 h
(−)-(S)-9a,
(−)-(S)-41 − (−)-(S)-49
(up to 86% ee)
Aryl,
Nr. of product,
and temp. →
9a
at −40°C
41
at −40°C
44
at −78°C
42
at −40°C
43
at room temp.
Reagent ↓
(1.0 equiv.)
93%; 62% ee
35%; 45% ee
94%; 68% ee
no conversion
28%; 0% ee
14%; 86% ee
MgO
Ph
35
Et3Zn
NMe2
72%; 63% ee
86%; 69% ee
trace; ee not measured 62%; 0% ee
70%; 79% ee
90%; 82% ee
(2.0 equiv.)
100%; 65% ee
50%; 69% ee
71%; 0% ee
(1.0 equiv.)
Aryl,
Nr. of product,
and temp. →
46
at −78°C
47
at −40°C
48
at −78°C
49
at −78°C
45
at −78°C
Reagent ↓
(1.0 equiv.)
trace; ee not measured 11%; 33% ee
trace; ee not measured 71%; 80% ee
trace; ee not measured
MgO
Ph
35
Et3Zn
NMe2
58% Ph−S(=O)−Et (9a), which
includes hydrodebromination;
51% ee
trace; ee not measured
50%; 78% ee
7%; 46% ee
58%; 78% ee
79%; 57% ee
100%; 82% ee
87%; 84% ee
(2.0 equiv.)
47%; 47% ee
+
31% Ph−S(=O)−Et (9a), which
includes hydrodebromination;
53% ee[a]
65%; 46% ee
(1.0 equiv.)
6
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
[a] The two sulfoxides were isolated separately after flash chromatography on silica gel[33].− Reagents and conditions: a), b): Same as a) and b), respectively, in the
caption of Table 4.
According to Table 5 the best conditions of our asymmetric
phenylsulfinylation of the ethyl-containing zincates 35 (Table 2,
entry 3 and Table 4, entry 5) and 40 (Table 4, entry 10) suited for
undertaking analogous arylsulfinylations, too. Each reaction was
tested using either 1.0 or 2.0 equiv. of Et3Zn⊖ ⊕[MgO-N-methyl-
Arylsulfinylations of Activated Dialkylzinc
Compounds Other Than Diethylzinc
(−)-ephedrinate] (35) or, alternatively, 1.0 equiv. of
2
Et4Zn⊖ [⊕MgO-N-methyl-(−)-ephedrinate]2 (40) in THF. The
Alkyl4Zn
MgO
Ph
OH
a)
NMe2
respective results are repeated in Table 5 at top and left.
The arylsulfinylations of Table 5 provided (S)-configured aryl ethyl
sulfoxides unexceptionally. They were realized at the lowest tem-
perature possible:[22] The relatively electron-poor diaryl sulfoxides
– containing chloro, bromo or aryl substituents – reacted at
−78°C. The relatively electron-rich diaryl sulfoxides – with methyl
or methoxy substituents – reacted at −40°C and the sterically de-
manding dimesityl sulfoxide 43 at room temperature. These aryl-
sulfinylations proceeded with considerable substrate and nucleo-
phile dependencies:
NMe2
Ph
in situ
2
18
O
S
O
S
Alkyl
THF, temp., 20 h
Cl
Cl
Cl
50
(−)-(S)-48,
(−)-(S)-51 - (−)-(S)-53, 54
Products:
O
O
O
S
S
S
1) Sulfinylating 1.0 equiv. of Et3Zn⊖ ⊕[MgO-N-methyl-(−)-ephedri-
nate] (35) there was only one good result: (−)-(S)-4-chlorophenyl
ethyl sulfoxide (48) was obtained in 71% yield with 80% ee. The
seemingly analogous aryl ethyl sulfoxides (−)-(S)-41 (35%, 45%
ee), 43 (28%, rac), (−)-(S)-44 (14%, 86% ee), and (−)-(S)-46
(11%, 33% ee) resulted in low yields and their ee values were
mediocre – except for (−)-(S)-44 (86% ee). The aryl ethyl sulfox-
ides 43, 45, 47, and 49 emerged at most in trace amounts, even
if their preparation was attempted at 22°C.
2) Sulfinylating 2.0 equiv. of Et3Zn⊖ ⊕[MgO-N-methyl-(−)-ephedri-
nate] (35) brought major improvements: The aryl ethyl sulfoxides
(−)-(S)-41, (−)-(S)-44, (−)-(S)-47, and (−)-(S)-48 were obtained in
good yields (50-100%) and good enantioselectivities (68-82%
ee). Sulfoxide 43 was obtained in 62% yield (yet once more race-
mic). The yield of sulfoxide (−)-(S)-46 was low again (7%) and the
sulfoxides 42 and 45 still not obtained. Bis(2-bromophenyl) sul-
foxide was a viable arylating reagent, too. However, a hydro-
debromination of the expected sulfoxide ensued under the reac-
tion conditions. Overall, this afforded the bromine-free sulfoxide
9a in 58% yield with 51% ee.
Cl
Cl
Cl
(−)-(S)-51
at 0°C
50%, 52% ee
(−)-(S)-48
at −78°C
87%, 84% ee
(−)-(S)-52
at −78°C
83%, 83% ee
O
O
S
S
Cl
Cl
(−)-(S)-53
at −78°C
98%, 29% ee
54
at room temp.
no conversion
Scheme 2. Asymmetric (“desymmetrizing”[11]) 4-chlorophenylations of tetraalkyl
rather than tetraethyl zincates juxtaposed by an N-methyl-(−)-ephedrine-based
magnesium β-aminoalkoxide counterion employing the symmetric bis(4-
chlorophenyl) sulfoxide (50) as a sulfinylating agent. The absolute configuration
of the resulting sulfoxides emerges from their levorotation. It correlates with
previously determined 3D structures [for (−)-51: ref.[42]; for (−)-48 and (−)-52:
ref.[12b]]. The absolute configuration of 4-chlorophenyl hexyl sulfoxide [(−)-53]
was determined after converting it through sulfoxide-magnesium exchange with
PhMgBr[44] – with inversion of configuration – into dextrorotatory hexyl phenyl
sulfoxide. The latter is (R)-configured according to ref.[46].− Reagents and
conditions: a) 18 (2.0 equiv.), Alkyl2Mg (2.0 equiv.), THF, room temp., 30 min;
Alkyl2Zn (1.0 equiv.), 10 min; this solution was added to a (precooled) solution
of 50 (−78°C for Alkyl = Et, Bu, and Hex; 0°C for Alkyl = Me, or room temp. for
Alkyl = Oct) and stirred for 20 h. The reaction was worked up with aqueous sat.
NH4Cl-solution and tBuOMe.
3) Sulfinylating 1.0 equiv. of the tetraorganozincate
Et4Zn2 [⊕MgO-N-methyl-(−)-ephedrinate]2 (40) with the diaryl
⊖
sulfoxides of Table 5 was our best procedure both in terms of yield
(47-100%) and enantiocontrol. The highest enantiomeric ex-
cesses were 84% for (−)-(S)-48 and 82% for (−)-(S)-44. They
were unmatched by the remaining sulfoxides (46-78% ee). Only
ethyl mesityl sulfoxide (43) arose as a racemic mixture. Bis(2-
bromophenyl) sulfoxide was partly a bromophenylating agent (→
brominated sulfoxide 49; isolated in 47% yield with 47% ee) and
partly a phenylating agent (→ bromine-free sulfoxide 9a; isolated
in 31% yield with 53% ee) because of some in-situ dehydrodebro-
mination 46 → 9a (cf. above).
The final variation of the asymmetric arylsulfinylations of our in-
vestigation altered the alkyl group of the tetraethylzincate 40 stud-
ied hitherto to Me, Bu, Hex, and Oct. That is, we studied the asym-
metric
sulfinylation
of
the
corresponding
zincates
Alkyl4Zn2⊖ [⊕MgO-N-methyl-(−)-ephedrinate]2.[32] The respective
sulfinylating agent was bis(4-chlorophenyl) sulfoxide (50; Scheme
2), not diphenyl sulfoxide (9a; cf. Table 2 - Table 4) because the
former sulfoxide was associated with the highest ee values of
Table 5.
The highest-yielding sulfinylations of Table 5 occurred at −78°C
and furnished the aryl hexyl sulfoxide (−)-(S)-53 (98% yield) and
the aryl butyl sulfoxide (−)-(S)-52 (83% yield). Surprisingly, the
respective ee values differed widely, being 29% and 83%. In
7
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
accordance with the lower nucleophilicity of Zn-bound Me vs.
higher alkyl groups,[18] the 4-chlorophenylsulfinylation of
Me4Zn2⊖ [⊕MgO-N-methyl-(−)-ephedrinate]2 had be performed at
0°C. It provided the sulfoxide (−)-(S)-51 in 50% yield with 52% ee.
In stark contrast to the ease of sulfinylation both of the tetrabutyl
zincate and the tetrahexyl zincate − at −78°C! − the tetraoctyl
zincate was not even sulfinylated at room temperature.
films spread on a NaCl plate. The ee values were determined by chiral
HPLC. Optical rotations were measured at 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.
Preparation of Reactants
Me2Zn, Et2Zn, EtMgCl, iPrMgMgCl, tBuMgCl, and PhMgBr were pur-
chased. The concentration of Alkyl2Zn was determined by titration with
iodine in a THF-solution of lithium chloride.[34] The concentration of
organomagnesium compounds was determined by titration with salicylic
aldehyde phenylhydrazone.[35]
Conclusions
We prepared – at least formally – trialkyl zincates containing one
Preparation of Me3SiCH2MgCl
equivalent of
a
Mg2⊕-bound enantiomerically pure β-
aminoalkoxide ligand; preferably, the latter was N-methyl-(−)-
ephedrinate. Likewise, we prepared – at least formally – tetraalkyl
zincates which contain two equivalents of Mg2⊕-bound N-methyl-
(−)-ephedrinate. Both kinds of zincates reacted with symmetric
diaryl sulfoxides such that one Zn-bound alkyl group was
arylsulfinylated asymmetrically. From a different vantage point the
starting diaryl sulfoxide was “desymmetrized” thereby.[11] The
mentioned arylsulfinylations rendered alkyl aryl sulfoxides in
yields up to 86% and with ee values up to 86%. This route to
enantiomerically enriched sulfoxides is novel and conceptionally
interesting. Developing it from needing stoichiometric amounts of
a homochiral additive at present to needing perhaps just catalytic
amounts thereof is an intriguing challenge for the future.
(Chloromethyl)trimethylsilan (2.80 ml, 2.45 g, 20.0 mmol) was added drop-
wise to Mg turnings (535 mg, 22.0 mmol, 1.1 equiv.) in THF (20 ml). After-
wards the mixture was refluxed for 3 h. Then, the solution of the Grignard
reagent was separated from residual Mg turnings with a canula. The re-
sulting solution of the Grignard reagent could be stored at 4°C for several
weeks. Its concentration was determined by titration with salicylic aldehyde
phenylhydrazone.[35]
Preparation of Et2Mg, (Me3SiCH2)2Mg, and Bu2Mg solutions in Et2O
At room temperature the appropriate alkyl bromide or chloride (128 mmol)
was added dropwise to a suspension of Mg turnings (3.14 g, 129 mmol,
1.0 equiv.) in Et2O (60 mL) within 1.5 h. The dark grey suspension was
heated under reflux for 4 h. After cooling to 0°C, diglyme (7.20 mL, 6.75 g,
50.3 mmol, 0.39 equiv.) in Et2O (9 mL) and thereafter dioxane (6.60 mL,
6.80 g, 77.2 mmol, 0.60 equiv.) in Et2O (6 mL) were added dropwise with
a syringe pump within 75 and 50 min, respectively. The white suspension
was stirred at −10°C for 16 h and then filtered with suction under an
atmosphere of nitrogen. The clear and colorless filtrate was concentrated
to about half its volume by a stream of nitrogen. Usually a small amount of
a white precipitate formed concomitantly; it remained in the solution
without decreasing its activity. The resulting solution of Alkyl2Mg could be
stored at 4°C for several weeks. Its concentration was determined by
titration with salicylic aldehyde phenylhydrazone.[35]
Experimental Section
Working technique: All reactions were carried out under an atmosphere
of N2. Prior to use reaction flasks were dried in vacuo with a heat gun.
Liquids were added with a syringe through a septum. Prior to use THF,
Et2O, hexane and toluene were distilled over sodium or potassium under
an atmosphere of N2. Other solvents and reagents were employed as ob-
tained commercially, i. e. without further purification. Flash chroma-
tography on silica gel: Purification by flash chromatography was
conducted on silica gel 60 (230-400 mesh). All eluents were distilled prior
to use. Chromatography conditions are documented in a shorthand form
like, e. g. “(c-C6H12:EtOAc a:b, fractions 10-20)”, which means we eluted
with an a:b mixture (v:v) of c-C6H12 and EtOAc 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.[33] Nuclear mag-
netic resonance spectra: Spectra were obtained on a NMR spectrometer
(400 MHz, and 300 MHz for 1H, 100 MHz for 13C, respectively); referenced
internally to the 1H- and 13C-NMR signals of the solvent [CDCl3: 7.26 ppm
(1H) and 77.10 ppm (13C)]. 1H-NMR data are reported as follows: chemical
shift (δ in ppm), multiplicity (s for singlet; d for doublet; t for triplet; q for
quartet; m for multiplet; mc for symmetric multiplet; br for broad signal),
coupling constant(s) (Hz), integral, assignment. 13C-NMR data are
reported in terms of chemical shift and assignment. Assignments of 1H
NMR and 13C NMR resonances refer to the IUPAC nomenclature except
within substituents (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. NMR Assignments were made using a combination of
1D and 2D techniques (DQF-COSY and ed-HSQC). High-resolution
mass spectra: These spectra were obtained in CI/NH3 (110 eV) or ESI
(spray 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
Preparation of Alkyl2Mg solutions in Et2O (Alkyl = Me, Hex, Ph)[36]
At room temperature AlkylLi (solution in THF, 12.0 mmol, 1.0 equiv.) was
added dropwise to a solution of AlkylMgCl (solution in THF, 12.0 mmol, 1.0
equiv.). After 5 min the solvent was removed by applying high vacuo (~ 0.4
mbar). The residue was extracted with Et2O (3 × 10 mL) from precipitated
LiCl. The concentration of the resulting clear and colorless solution was
determined by titration with salicylic aldehyde phenylhydrazone.[35] At 4°C
such solutions could be stored for several weeks.
Preparation of Bu2Zn and Hex2Zn[37]
At 0°C nBuLi or nHexLi (solutions in hexane, 18.7 mmol, 2.0 equiv.) was
added dropwise to dry ZnCl2 (1.28 g, 9.35 mmol) in Et2O (10 ml). After 4 h
at 0°C the solvent was evaporated in a stream of nitrogen. The residue
was taken up in dry hexane (10 ml). The clear supernatant was separated
from the precipitate with a canula and transferred into a dry Schlenk flask.
The solution was stored at 4°C for several weeks. Its concenctration was
determined by titration with iodine in a THF-solution of lithium chloride.[34]
Preparation of Oct2Zn[38]
At room temp. BEt3 (1.0
BH3 . THF (1.0
in THF, 1.0 ml, 1.0 mmol, 0.33 equiv.) were premixed for
5 min. 1-Octene (0.47 ml, 337 mg, 3.0 mmol) was added dropwise to the
resulting solution of HBEt2 (1.0 in THF, 3.0 ml, 3.0 mmol, 1.0 equiv.) at
0°C and stirred for 3 h at 0°C. Then, the solvent was evaporated in high
vacuo at room temp. before ZnEt2 (0.76 in hexane, 7.9 ml, 6.0 mmol,
2.0 equiv.) was added dropwise. This mixture was stirred for 30 min and
M in THF, 2.0 ml, 2.0 mmol, 0.66 equiv.) and
M
M
M
8
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
the solvent was evaporated once again in high vacuo. The residue was
taken up in THF (3 ml). The solution (quantitative yield) was stored at 4°C
for several weeks. Its concenctration was determined by titration with
iodine in a THF solution of lithium chloride.[34]
precooled (for temperature cf. individual descriptions) solution of the diaryl
sulfoxide (0.223 mmol) in THF (1.0 ml). When the reaction was finished
(typically 20 h), the reaction was stopped by the addition of MeOH (1 ml)
and aqueous sat. NH4Cl-solution (1 ml). The layers were separated and
the aqueous layer was extracted with t-BuOMe (3 × 2 ml). The combined
organic layers were dried over MgSO4 and evaporated. The crude product
was purified by flash chromatography on silica gel[33] to yield the title
compound (for details on flash chromatography, yields, ee, and deviations
from this procedure: cf. individual descriptions).
Preparation of Substrates and Alkyl Aryl Sulfoxides
The symmetric diaryl sulfoxides and the racemic alkyl aryl sulfoxides ex-
cept rac-51 and rac-53 were materials from our previous study.[12b] The
synthesis of the enantiopure aminoalcohols is disclosed in the Supporting
Information.
(−)-(S)-Ethyl Phenyl Sulfoxide (9a)
O
General Procedure for the Racemic Phenylsulfinylation of
RnEt2Znn⊖ Mn⊕ (cf. Table 1)
The asymmetric synthesis was accomplished at −40°C
over 20 h either using 1.0 equiv. of Et3Zn⊖ ⊕[magnesio
N-methyl-(−)-ephedrinate] under the conditions of
“Treatment A” [except for using more sulfoxide
(namely 80.0 mg, 0.396 mmol); which delivered (−)-
S
At room temp. R−M (in THF or Et2O; 0.223 mmol, 1.0 equiv. for n = 1 or
1'
0.446 mmol, 2.0 equiv. for n = 2) was added to a solution of ZnEt2 (0.93
M
in hexane, 0.24 ml, 0.223 mmol, 1.0 equiv.) in THF (1 ml). After 10 min
diphenyl sulfoxide (9a, 45.1 mg, 0.223 mmol) was added in one portion.
After the time indicated in Table 1 the reaction was stopped by the addition
of MeOH (1 ml) and aqueous sat. NH4Cl-solution (1 ml). The layers were
separated and the aqueous layer was extracted with t-BuOMe (3 × 2 ml).
The combined organic layers were dried over MgSO4 and evaporated. The
crude product was purified by flash chromatography on silica gel[33] to yield
the title compound (for details on flash chromatography, yields, ee, and
deviations from this procedure: cf. individual descriptions).
(S)-9a (57.0 mg, 0.370 mmol, 93%, 62% ee)] or using 2.0 equiv. of Et3Zn⊖
⊕[magnesio N-methyl-(−)-ephedrinate] under the conditions of “Treat-
ment B” [except for using more sulfoxide (namely 80.0 mg, 0.396 mmol);
which delivered (−)-(S)-9a (43.8 mg, 0.284 mmol, 72%, 63% ee)] or using
1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]2 under the
conditions of “Treatment C” [which delivered (−)-(S)-9a (29.6 mg,
0.192 mmol, 86%, 69% ee)]. This product was purified by flash
chromatography on silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 55:45,
fractions 27-42) and obtained as a colorless oil. 1H NMR (300.1 MHz,
CDCl3): δ = 1.20 (dd, J2‘,1‘-A = J2‘,1‘-B = 7.4 Hz, 3H, 2‘-H3), AB signal (δA
=
General Procedure for the Asymmetric Arylsulfinylation of 1.0 equiv.
2.77, δB = 2.90, JA,B = 13.2 Hz, A part additionally split by q, J1‘-A,2‘ = 7.4
Hz, 1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.4 Hz, 1‘-HB), 7.48-7.56
(m, 3H, 3 × Ar-H), 7.59-7.65 ppm (m, 2H, 2 × Ar-H). The preceding data
were reported by us earlier.[12b] The ee was determined by chiral HPLC
(Chiralcel OD-3, n-heptane/iPrOH 96:4, 1 mL/min, λdetector = 208 nm): tr(R)
= 11.79 min, tr(S) = 15.59 min. Optical rotation: ꢀꢁꢂꢆꢃꢄꢇꢅ ꢈ −125.3 (c = 1.32
in CHCl3; a sample with 69% ee was used); ref.[39]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −219.6 [c =
1.4 in EtOH, a sample of the (S)-enantiomer with 99% ee]. The absolute
configuration was determined by comparing the sense of the optical
rotation with literature data.[39]
of Et3Zn⊖ ⊕[Magnesio N-Methyl-(−)-ephedrinate] – “Treatment A”
At room temp. Et2Mg (0.54
added dropwise to a solution of N-methyl-(−)-ephedrine (18, 40.0 mg,
0.223 mmol, 1.0 equiv.) in THF (1 ml). After 30 min Et2Zn (0.93 in
M in Et2O, 0.41 ml, 0.223 mmol, 1.0 equiv) was
M
hexane, 0.24 ml, 0.223 mmol, 1.0 equiv.) was added and stirred for
another 10 min. This freshly prepared solution was added dropwise to a
precooled (for temperature cf. individual descriptions) solution of the diaryl
sulfoxide (0.223 mmol) in THF (1.0 ml). When the reaction was finished
(typically 20 h), the reaction was stopped by the addition of MeOH (1 ml)
and aqueous sat. NH4Cl-solution (1 ml). The layers were separated and
the aqueous layer was extracted with t-BuOMe (3 × 2 ml). The combined
organic layers were dried over MgSO4 and evaporated. The crude product
was purified by flash chromatography on silica gel[33] (details: cf. individual
descriptions) to yield the title compound.
(−)-(S)-Ethyl pTolyl Sulfoxide (41)
The asymmetric synthesis was accomplished at
−40°C over 20 h either using 1.0 equiv. of Et3Zn⊖
⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment A” [which delivered (−)-
(S)-41 (13.0 mg, 77.0 µmol, 35%, 45% ee)], or
O
S
1'
General Procedure for the Asymmetric Arylsulfinylation of 2.0 equiv.
of Et3Zn⊖ ⊕[Magnesio N-Methyl-(−)-ephedrinate] – “Treatment B”
using 2.0 equiv. of Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate] under
the conditions of “Treatment B” [which delivered (−)-(S)-41 (35.3 mg,
0.210 mmol, 94%, 68% ee)], or using 1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-
methyl-(−)-ephedrinate]2 under the conditions of “Treatment C” [which
delivered (−)-(S)-41 (37.5 mg, 0.223 mmol, 100%, 65% ee)]. This product
was purified by flash chromatography on silica gel[33] (3 cm, 20 ml, c-
C6H12:AcOEt 50:50, fractions 18-29) and obtained as a colorless oil. 1H
NMR (300.1 MHz, CDCl3): δ = 1.19 (dd, J2‘,1‘-A = J2‘,1‘-B = 7.4 Hz, 3H, 2‘-H3),
AB signal (δA = 2.76, δB = 2.87, JA,B = 13.2 Hz, A part additionally split by
q, J1‘-A,2‘ = 7.4 Hz, 1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.5 Hz, 1‘-
HB), AA’BB’ signal with signal centers at δA = 7.32 and δB = 7.50 ppm (4H,
2 × 2-H and 2 × 3-H). The preceding data were reported by us earlier.[12b]
The ee was determined by chiral HPLC (Chiralcel OJ-H, n-heptane/EtOH
At room temp. Et2Mg (0.54
added dropwise to a solution of N-methyl-(−)-ephedrine (18, 80.0 mg,
0.446 mmol, 2.0 equiv.) in THF (1 ml). After 30 min Et2Zn (0.93 in
M in Et2O, 0.82 ml, 0.446 mmol, 2.0 equiv.) was
M
hexane, 0.48 ml, 0.446 mmol, 2.0 equiv.) was added and stirred for
another 10 min. This freshly prepared solution was added dropwise to a
precooled (for temperature cf. individual descriptions) solution of the diaryl
sulfoxide (0.223 mmol) in THF (1.0 ml). When the reaction was finished
(typically 20 h), the reaction was stopped by the addition of MeOH (1 ml)
and aqueous sat. NH4Cl-solution (1 ml). The layers were separated and
the aqueous layer was extracted with t-BuOMe (3 × 2 ml). The combined
organic layers were dried over MgSO4 and evaporated. The crude product
was purified by flash chromatography on silica gel[33] to yield the title
compound (for details on flash chromatography, yields, ee, and deviations
from this procedure: cf. individual descriptions).
98:2, 1 mL/min, λdetector = 232 nm): tr(R) = 17.13 min, tr(S) = 20.26 min.
ꢆꢇ
Optical rotation: ꢀꢁꢂ
ꢈ −153.1 (c = 1.04 in CHCl3; a sample with 68%
ꢃꢄꢅ
ee was used); ref.[40]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −247 [c = 2.6 in CHCl3, a sample of the (S)-
enantiomer with 94% ee]. The absolute configuration was determined by
comparing the sense of the optical rotation with literature data.[12b],[39]
General Procedure for the Asymmetric Arylsulfinylation of 1.0 equiv.
of Alkyl4Zn2⊖ ⊕[Magnesio N-Methyl-(−)-ephedrinate]2 – “Treatment C”
At room temp. Alkyl2Mg (solution in Et2O, 0.82 ml, 0.446 mmol, 2.0 equiv.)
was added dropwise to a solution of N-methyl-(−)-ephedrine (18, 80.0 mg,
0.446 mmol, 2.0 equiv.) in THF (1 ml). After 30 min Alkyl2Zn (solution in
hexane, 0.24 ml, 0.223 mmol, 1.0 equiv.) was added and stirred for
another 10 min. This freshly prepared solution was added dropwise to a
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
269 nm): tr(S) = 32.31 min, tr(R) = 35.51 min. Optical rotation: ꢀꢁꢂꢃꢆꢄꢇꢅ
ꢈ
:
−207.3 (c = 1.59 in CHCl3; a sample with 86% ee was used); ref.[12b]
(−)-(S)-(2,4-Dimethylphenyl) Ethyl Sulfoxide (42)
ꢆꢇ
ꢀꢁꢂ
ꢈ −145.4 [c = 1.4 in EtOH, a sample of the (S)-enantiomer with 70%
ꢃꢄꢅ
The asymmetric synthesis was accomplished at
O
ee]. The absolute configuration was determined by comparing the sense
of the optical rotation with literature data.[12b]
−40°C over 20 h using 1.0 equiv. of Et4Zn2
⊖
S
3
⊕[magnesio N-methyl-(−)-ephedrinate]2 under the
conditions of “Treatment C” [which delivered (−)-
(S)-42 (20.4 mg, 0.112 mmol, 50%, 69% ee)]. This
product was purified by flash chromatography on
1'
(−)-(S)-Ethyl (1-Naphthyl) Sulfoxide (45)
6
5
The asymmetric synthesis was accomplished at
−78°C over 20 h using 1.0 equiv. of Et4Zn2
O
⊖
silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 55:45, fractions 18-30) and ob-
tained as a colorless oil. 1H NMR (300.1 MHz, CDCl3): δ = 1.23 (dd, J2‘,1‘-A
= J2‘,1‘-B = 7.5 Hz, 3H, 2‘-H3), 2.34 (s, 3H, Ar-CH3), 2.36 (s, 3H, Ar-CH3), AB
signal (δA = 2.71, δB = 2.86, JA,B = 13.3 Hz, A part additionally split by q,
J1‘-A,2‘ = 7.4 Hz, 1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.5 Hz, 1‘-HB),
7.01 (mc, 1H, 3-H), 7.22 (mc, J5,6 = 7.9 Hz, 1H, 5-H), 7.75 ppm (d, J6‘,5‘
8.1 Hz, 1H, 6-H). The preceding data were reported by us earlier.[12b] The
ee was determined by chiral HPLC (Chiralpak AD-3, n-heptane/EtOH
90:10, 1 mL/min, λdetector = 204 nm): tr(R) = 8.46 min, tr(S) = 11.79 min.
⊕[magnesio N-methyl-(−)-ephedrinate]2 under the
conditions of “Treatment C” [which delivered (−)-
(S)-45 (23.0 mg, 0.113 mmol, 51%, 78% ee)]. This
S
1'
product was purified by flash chromatography on silica gel[33] (3 cm, 20 ml,
c-C6H12:AcOEt 55:45, fractions 11-16) and obtained as a colorless oil. 1H
NMR (300.1 MHz, CDCl3¸the sample contains a trace of grease with s at
1.25 ppm): δ = 1.22 (dd, J2‘,1‘-A = J2‘,1‘-B = 7.4 Hz, 3H, 2‘-H3), AB signal (δA
= 2.85, δB = 3.12, JA,B = 13.6 Hz, A part additionally split q, J1‘-A,2‘ = 7.4 Hz,
1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.4 Hz, 1‘-HB), 7.58 (mc, 2H, 2
=
ꢆꢇ
Optical rotation: ꢀꢁꢂ
ꢈ −193.6 (c = 0.55 in CHCl3; a sample with 69%
ꢃꢄꢅ
3
3
ee was used); ref.[12b]: ꢀ ꢁꢂꢃꢆꢄꢇꢅ ꢈ −248.7 [c = 1.64 in EtOH, a sample of the
(S)-enantiomer with 96% ee]. The absolute configuration was determined
by comparing the sense of the optical rotation with literature data.[12b]
× Ar-H), 7.67 (dd, J = 8.2 Hz, J = 7.0 Hz, 1H, 1 × Ar-H), 7.92-7.99 (m,
3H, 3 × Ar-H), 8.11 ppm (dd, 3J = 7.2 Hz, 4J = 1.2 Hz, 1H, 1 × Ar-H). The
preceding data were reported by us earlier.[12b] The ee was determined by
chiral HPLC (Chiralcel OJ-H, n-heptane/iPrOH 80:20, 1 mL/min, λdetector
224 nm): tr(R) = 6.85 min, tr(S) = 7.62 min. Optical rotation: ꢀꢁꢂꢃꢆꢄꢇꢅ
=
ꢈ
:
rac-Ethyl (2,4,6-Trimethylphenyl) Sulfoxide (43)
−161.8 (c = 1.25 in CHCl3; a sample with 78% ee was used); ref.[12b]
ꢆꢇ
O
S
The synthesis was accomplished at room temp.
over 20
either using 1.0 equiv. of Et3Zn⊖
⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment A” [which delivered rac-
43 (12.3 mg, 63.0 µmol, 28%)], or using 2.0 equiv.
of Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]
ꢀꢁꢂ
ꢈ −248.7 [c = 1.40 in EtOH, a sample of the (S)-enantiomer with
ꢃꢄꢅ
h
93% ee]. The absolute configuration was determined by comparing the
sense of the optical rotation with literature data.[12b]
3
1'
5
(−)-(S)-Ethyl (2-Naphthyl) Sulfoxide (46)
The asymmetric synthesis was accomplished at
−78°C over 20 h either using 1.0 equiv. of
Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]
under the conditions of “Treatment A” [which
delivered (−)-(S)-46 (5.0 mg, 25 µmol, 11%,
O
under the conditions of “Treatment B” [which delivered rac-43 (27.1 mg,
0.138 mmol, 62%)], or using 1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-methyl-
(−)-ephedrinate]2 under the conditions of “Treatment C” [which delivered
rac-43 (31.2 mg, 0.159 mmol, 71%)]. This product was purified by flash
chromatography on silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 55:45,
fractions 21-31) and obtained as a colorless oil. 1H NMR (300.1 MHz,
CDCl3): δ = 1.28 (dd, J2‘,1‘-A = J2‘,1-B = 7.5 Hz, 3H, 2‘-H3), 2.28 (s, 3H, Ar-
CH3), 2.54 (s, 6H, 2 × Ar-CH3), AB signal (δA = 2.94, δB = 3.22, JA,B = 12.9
Hz, A part additionally split by q, J1‘-A,2‘ = 7.6 Hz, 1‘-HA; B part additionally
split by q, J1‘-B,2‘ = 7.6 Hz, 1‘-HB), 6.86 ppm (s, 2H, 2 × Ar-H). The preceding
data were reported by us earlier.[12b] The ee was determined by chiral
HPLC (Chiralcel OD-3, n-heptane/iPrOH 98:2, 1 mL/min, λdetector = 205
nm): tr(1) = 11.86 min, tr(2) =19.57 min.
1
S
1'
33% ee)], or using 2.0 equiv. of Et3Zn⊖ ⊕[magnesio N-methyl-(−)-
ephedrinate] under the conditions of “Treatment B” [which delivered (−)-
(S)-46 (3.5 mg, 17 µmol, 7%, 46% ee)], or using 1.0 equiv. of Et4Zn2
⊖
⊕[magnesio N-methyl-(−)-ephedrinate]2 under the conditions of “Treat-
ment C” [which delivered (−)-(S)-46 (29.4 mg, 0.144 mmol, 65%, 46%
ee)]. This product was purified by flash chromatography on silica gel[33]
(3 cm, 20 ml, c-C6H12:AcOEt 55:45, fractions 15-33) and obtained as a
colorless oil. 1H NMR (300.1 MHz, CDCl3): δ = 1.22 (dd, J2‘,1‘-A = J2‘,1‘-B
=
7.5 Hz, 3H, 2‘-H3), AB signal (δA = 2.84, δB = 3.00, JA,B = 13.3 Hz, A part
additionally split by q, J1‘-A,2‘ = 7.4 Hz, 1‘-HA; B part additionally split by q,
J1‘-B,2‘ = 7.5 Hz, 1‘-HB), 7.55-7.62 (m, 3H, 3 × Ar-H), 7.89-7.99 (m, 3H, 3 ×
Ar-H), 8.18 ppm (d, J1,8 = 1.8 Hz, 1H, 1-H). The preceding data were
reported by us earlier.[12b] The ee was determined by chiral HPLC
(Chiralcel OJ-H, n-heptane/EtOH 95:5, 1 mL/min, λdetector = 232 nm): tr(R)
= 16.12 min, tr(S) = 16.90 min. Optical rotation: ꢀꢁꢂꢆꢃꢄꢇꢅ ꢈ −75.3 (c = 0.59
in CHCl3; a sample with 46% ee was used); ref.[12b]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −99.8 [c =
(−)-(S)-Ethyl (4-Phenylphenyl) Sulfoxide (44)
The asymmetric synthesis was accomplished at
−78°C over 20 h either using 1.0 equiv. of Et3Zn⊖
⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment A” [except for using
more sulfoxide (namely 163.8 mg, 0.462 mmol);
O
S
1'
Ph
0.49 in EtOH, a sample of the (S)-enantiomer with 66% ee] or ref.[39]
:
which delivered (−)-(S)-44 (14.4 mg, 63.0 µmol, 14%, 86% ee)], or using
2.0 equiv. of Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment B” [which delivered (−)-(S)-44 (35.8 mg,
0.155 mmol, 70%, 79% ee)], or using 1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-
methyl-(−)-ephedrinate]2 under the conditions of “Treatment C” [which
delivered (−)-(S)-44 (46.3 mg, 0.201 mmol, 90%, 82% ee)]. This product
was purified by flash chromatography on silica gel[33] (3 cm, 20 ml, c-
C6H12:AcOEt 50:50, fractions 18-30) and obtained as a colorless oil. 1H
NMR (300.1 MHz, CDCl3): δ = 1.24 (dd, J2‘‘,1‘‘-A = J2‘‘,1‘‘-B = 7.4 Hz, 3H, 2‘‘-
H3), AB signal (δA = 2.82, δB = 2.95, JA,B = 13.3 Hz, A part additionally split
by q, J1‘‘-A,2‘‘ = 7.4 Hz, 1‘‘-HA; B part additionally split by q, J1‘‘-B,2‘‘ = 7.5 Hz,
1‘‘-HB), 7.37-7.42 (m, 1 H, 4‘-H), 7.45-7.50 (m, 2H, 2 × 2‘-H*), 7.59-7.62
ꢆꢇ
ꢀꢁꢂ
ꢈ −180.5 [c = 1.3 in acetone, a sample of the (S)-enantiomer with
ꢃꢄꢅ
>99% ee]. The absolute configuration was determined by comparing the
sense of the optical rotation with literature data.[12b],[39]
(−)-(S)-Ethyl (4-Methoxyphenyl) Sulfoxide (47)
The asymmetric synthesis was accomplished
at −40°C over 20 h either using 2.0 equiv. of
Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]
under the conditions of “Treatment B” [which
O
S
1'
delivered (−)-(S)-47 (22.3 mg, 0.131 mmol,
MeO
58%, 78% ee)], or using 1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-methyl-(−)-
ephedrinate]2 under the conditions of “Treatment C” [which delivered (−)-
(S)-47 (29.8 mg, 0.175 mmol, 79%, 57% ee)]. This product was purified by
flash chromatography on silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 40:60,
(m, 2H, 2 × 3‘-H*), AA’BB‘ signal with signal centers at δA = 7.68 and δB
7.75 ppm (4H, 2 × 2-H and 2 × 3-H); *assignments interchangeable. The
preceding data were reported by us earlier.[12b] The ee was determined by
=
chiral HPLC (Chiralpak AD-3, n-heptane/iPrOH 95:5, 1 mL/min, λdetector
=
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
fractions 23-34) and obtained as a colorless oil. 1H NMR (300.1 MHz,
The racemic synthesis was accomplished by
O
CDCl3): δ = 1.18 (dd, J2‘,1‘-A = J2‘,1‘-B = 7.5 Hz, 3H, 2‘-H3), AB signal (δA
=
mixing MeMgCl (2.37
M
in THF, 0.26 ml,
S
2.78, δB = 2.84, JA,B = 13.1 Hz, A part additionally split q, J1‘-A,2‘ = 7.5 Hz,
1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.5 Hz, 1‘-HB), 3.86 (s, 3H, O-
CH3), AA’BB‘ signal with signal centers at δA = 7.03 and δB = 7.55 ppm
(4H, 2 × 2-H and 2 × 3-H). The preceding data were reported by us
earlier.[12b] The ee was determined by chiral HPLC (Chiralcel OD-3, n-
0.615 mmol, 1.0 equiv.) with bis(4-chlorophenyl)
sulfoxide (167 mg, 0.615 mmol) in THF (2 ml) at
room temperature. After 1 h the mixture was
Cl
quenched by the addition of aqueous sat. NH4Cl-solution (2 ml). The
workup was carried out in analogy to the asymmetric synthesis (cf. general
procedures above). This led to rac-51 (48.7 mg, 0.279 mmol, 45%). The
asymmetric synthesis was accomplished at 0°C over 20 h using
1.0 equiv. of Me4Zn2⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]2 under the
conditions of “Treatment C” [which delivered (−)-(S)-51 (19.5 mg,
0.112 mmol, 50%, 52% ee)]. This product was purified by flash
chromatography on silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 50:50,
fractions 23-39) and obtained as a colorless oil. 1H NMR (300.1 MHz,
CDCl3): δ = 2.72 (s, 3H, CH3), AA’BB’-signal with signal centers at 7.51
and 7.60 ppm (4H, 4 × Ar-H). The preceding data are consistent with those
reported in the literature.[41] The ee was determined by chiral HPLC (LC-
3, n-heptane/EtOH 85:15, 0.8 mL/min, λdetector = 254 nm): tr(R) = 8.98 min,
tr(S) = 10.05 min. Optical rotation: ꢀꢁꢂꢆꢃꢄꢇꢅ ꢈ −44.5 (c = 1.10 in CHCl3; a
sample with 52% ee was used); ref.[42]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −152.6 [c = 0.95 in CHCl3,
a sample of the (S)-enantiomer with 89% ee]. The absolute configuration
was determined by comparing the sense of the optical rotation with
literature data.[42]
heptane/iPrOH 96:4, 1 mL/min, λdetector = 204 nm): tr(R) = 10.68 min, tr(S)
ꢆꢇ
= 22.65 min. Optical rotation: ꢀꢁꢂ
ꢈ −139.3 (c = 0.70 in CHCl3; a
ꢃꢄꢅ
sample with 78% ee was used); ref.[12b]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −161.8 [c = 0.82 in EtOH,
a sample of the (S)-enantiomer with 81% ee]. The absolute configuration
was determined by comparing the sense of the optical rotation with
literature data.[12b]
(−)-(S)-(4-Chlorophenyl) Ethyl Sulfoxide (48)
The asymmetric synthesis was accomplished at
−78°C over 20 h either using 1.0 equiv. of Et3Zn⊖
⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment A” [except for using
more sulfoxide (namely 131 mg, 0.483 mmol);
O
S
1'
Cl
which delivered (−)-(S)-48(64.3 mg, 0.341 mmol, 71%, 80% ee)], or using
2.0 equiv. Et3Zn⊖ ⊕[magnesio N-methyl-(−)-ephedrinate] under the
conditions of “Treatment B” [which delivered (−)-(S)-48 (41.9 mg,
0.222 mmol, 100%, 82% ee)], or using 1.0 equiv. of Et4Zn2⊖ ⊕[magnesio N-
methyl-(−)-ephedrinate]2 under the conditions of “Treatment C” [which
delivered (−)-(S)-48 (36.8 mg, 0.195 mmol, 87%, 84% ee)]. This product
was purified by flash chromatography on silica gel[33] (3 cm, 20 ml, c-
C6H12:AcOEt 55:45, fractions 18-33) and obtained as a colorless oil. 1H
NMR (300.1 MHz, CDCl3): δ = 1.19 (dd, J2‘,1‘-A = J2‘,1‘-B = 7.4 Hz, 3H, 2‘-H3),
AB signal (δA = 2.74, δB = 2.90, JA,B = 13.3 Hz, A part additionally split by
q, J1‘-A,2‘ = 7.4 Hz, 1‘-HA; B part additionally split by q, J1‘-B,2‘ = 7.4 Hz, 1‘-
HB), AA’BB‘ signal with signal centers at δA = 7.50 and δB = 7.56 ppm (4H,
2 × 2-H and 2 × 3-H). The preceding data were reported by us earlier.[12b]
The ee was determined by chiral HPLC (Chiralpak AD-3, n-heptane/EtOH
(−)-(S)-Butyl (4-Chlorophenyl) Sulfoxide (52)
The asymmetric synthesis was accom-
O
plished at −78°C over 20
1.0 equiv. of Bu4Zn2 ⊕[magnesio N-
h using
4'
S
⊖
1'
methyl-(−)-ephedrinate]2 under
conditions of “Treatment C” [which
the
Cl
delivered (−)-(S)-52 (40.4 mg, 0.186 mmol, 83%, 83% ee)]. This product
was purified by flash chromatography on silica gel[33] (3 cm, 20 ml, c-
C6H12:AcOEt 75:25, fractions 15-27) and obtained as a colorless oil. 1H
NMR (300.1 MHz, CDCl3): δ = 0.92 (t, J4‘,3‘ = 7.5 Hz, 3H, 4‘-H3), 1.35-1.81
(m, 4H, 2‘- and 3‘-H2), 2.74-2.80 (m, 2H, 1’-H2), AA’BB‘ signal with signal
centers at δA = 7.50 and δB = 7.56 ppm (4H, 2 × 2-H and 2 × 3-H). The
preceding data were reported by us earlier.[12b] The ee was determined by
chiral HPLC (Chiralcel OD-3, n-heptane/iPrOH 96:4, 1.0 mL/min, λdetector
95:5, 1 mL/min, λdetector = 230 nm): tr(S) = 14.96 min, tr(R) = 17.64 min.
ꢆꢇ
Optical rotation: ꢀꢁꢂ
ꢈ −167.2 (c = 0.87 in CHCl3; a sample with 84%
ꢃꢄꢅ
ee was used); ref.[12b]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −161.8 [c = 0.82 in EtOH, a sample of the
(S)-enantiomer with 81% ee]. The absolute configuration was determined
by comparing the sense of the optical rotation with literature data.[12b]
= 222 nm): tr(R) = 8.30 min, tr(S) = 9.75 min. Optical rotation: ꢀꢁꢂꢃꢆꢄꢇꢅ
−121.5 (c = 3.40 in CHCl3; a sample with 52% ee was used); ref.[12b]
ꢈ
:
ꢆꢇ
ꢀꢁꢂ
ꢈ −61.1 [c = 0.90 in EtOH, a sample of the (S)-enantiomer with 29%
ꢃꢄꢅ
(−)-(S)-(2-Bromophenyl) EthylSulfoxide (49)
ee]. The absolute configuration was determined by comparing the sense
The asymmetric synthesis was accomplished at
−78°C over 20
⊕[magnesio N-methyl-(−)-ephedrinate]2 under the
conditions of “Treatment C” [which delivered (−)-(S)-
49 (24.5 mg, 0.105 mmol, 47%, 47% ee)]. This
product was purified by flash chromatography on
O
of the optical rotation with literature data.[12b]
Br
h
using 1.0 equiv. of Et4Zn2
⊖
S
3
4
1'
(−)-(S)-(4-Chlorophenyl) Hexyl Sulfoxide (53)
The racemic synthesis was
6
5
O
accomplished by mixing HexLi
6'
silica gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 70:30, fractions 12-17) and
obtained as a colorless oil. 1H NMR (300.1 MHz, CDCl3): δ = 1.25 (dd, J2‘,1‘-
A = J2‘,1‘-B = 7.4 Hz, 3H, 3‘-H3), AB signal (δA = 2.85, δB = 3.13, JA,B = 13.6
Hz, A part additionally split by q, J1‘-A,2‘ = 7.4 Hz, 1‘-HA; B part additionally
split by q, J1‘-B,2‘ = 7.5 Hz, 1‘-HB), 7.36 (ddd, 3J = 8.8 Hz, 3J = 7.7 Hz, 4J =
1.7 Hz, 1H, 4- or 5-H), 7.52-7.58 (m, 2H, 2 × Ar-H), 7.86 ppm (dd, 3J = 8.2
(2.54
0.597 mmol, 1.0 equiv.) with
bis(4-chlorophenyl) sulfoxide
(162 mg, 0.597 mmol) in THF
M in hexane, 0.24 ml,
S
1'
Cl
(2 ml) at room temperature. After 1 h the mixture was quenched by the
addition of aqueous sat. NH4Cl-solution (2 ml). The workup was carried
out in analogy to the asymmetric synthesis (cf. general procedures above).
This led to rac-53 (117 mg, 0.448 mmol, 80%). The asymmetric
synthesis was accomplished at −78°C over 20 h using 1.0 equiv.
Hex4Zn2⊖ ⊕[magnesio N-methyl-(−)-ephedrinate]2 under the conditions of
“Treatment C” [which delivered (−)-(S)-53 (53.6 mg, 0.219 mmol, 98%,
29% ee)]. This product was purified by flash chromatography on silica
gel[33] (3 cm, 20 ml, c-C6H12:AcOEt 75:25, fractions 15-27) and obtained
as a colorless oil. 1H NMR (300.1 MHz, CDCl3): δ = 0.87 (mc, 3H, 6-H3),
1.18-1.83 (m, 8H, 2-H2 to 5-H2), 2.77 (mc, 2H, 1-H2), AA’BB’-signal with
signal centers at 7.50 and 7.56 ppm (4H, 4 × Ar-H). The literature spectrum
was measured in CCl4.[43] The ee was determined by chiral HPLC
(Chiralcel OD-3, n-heptane/iPrOH 96:4, 1.0 mL/min, λdetector = 222 nm):
tr(R) = 8.30 min, tr(S) = 9.75 min. Optical rotation: ꢀꢁꢂꢆꢃꢄꢇꢅ ꢈ −121.5
4
Hz, J = 1.9 Hz, 1H, 3- or 6-H). The preceding data were reported by us
earlier.[12b] The ee was determined by chiral HPLC (Chiralpak AD-3, n-
heptane/EtOH 95:5, 1 mL/min, λdetector = 204 nm): tr(S) = 8.90 min, tr(R) =
ꢆꢇ
12.18 min. Optical rotation: ꢀꢁꢂ
ꢈ −122.4 (c = 2.01 in CHCl3; a sample
ꢃꢄꢅ
with 47% ee was used); ref.[12b]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ −239.5 [c = 0.62 in EtOH, a
sample of the (S)-enantiomer with 89% ee]. The absolute configuration
was determined by comparing the sense of the optical rotation with
literature data.[12b]
(−)-(S)-(4-Chlorophenyl) Methyl Sulfoxide (51)
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
(c = 3.40 in CHCl3; a sample with 52% ee was used). The absolute
configuration was determined by chemical correlation:[44] PhMgBr
in CHCl3); ref.[46]: ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ +37.6 [c = 0.25 in CHCl3, a sample of the (R)-
enantiomer with 25% ee]. The absolute configuration was determined by
comparing the sense of the optical rotation with literature data.[45]
(2.7
M in Et2O, 80 µl, 0.21 mmol) was added dropwise to a solution of (−)-
53 (19.0 mg, 78.0 µmol) in THF (0.5 ml) at room temperature. After 3 h the
reaction was quenched by the addition of aqueous sat. NH4Cl-solution
(1 ml). The layers were separated and the aqueous layer was extracted
with t-BuOMe (3 × 2 ml). The combined organic layers were dried over
MgSO4 and evaporated. The crude product was purified by flash
chromatography on silica[33] (1.5 cm, 8 ml, c-C6H12:AcOEt 92:8, fractions
34-46) to yield (+)-(R)-hexyl phenyl sulfoxide (5.3 mg, 25 µmol, 32%) as a
colorless oil. Since such a sulfinylation is known to proceed under
inversion of the configuration[44], the starting material (−)-53 had to be (S)-
configured. 1H NMR (300.1 MHz, CDCl3): δ = 0.86 (mc, 3H, 6’-H3), 1.20-
1.77 (m, 8H, 2’-, 3’-, 4’-, and 5’-H2), 2.75-2.81 (m, 2H, 1’-H2), 7.47-7.55 (m,
3H, 3 × Ar-H), 7.59-7.64 ppm (m, 2H, 2 × Ar-H). The preceding data are
consistent with those reported in the literature.[45] : ꢀꢁꢂꢃꢆꢄꢇꢅ ꢈ +38.3 (c = 0.37
Acknowledgments
The authors thank the Deutsche Forschungsgemeinschaft
(project BR 881-7) for financial support.
Keywords: desymmetrization • enantioselectivity • ephedrine •
organozincates
exchange
• sulfinylation • sulfoxides • sulfoxide-zinc
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a
phenylsulfinylation of Et2Zn since our trialkyl zincates proved to be reactive
enough and did not need further activation.
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[20] We are not sure whether trialkyl zincates form at all – and, if so, whether
they react as such or whether they equilibrate with dialkylzinc reagents and
the respective alkylmagnesium N-methyl-(−)-ephedrinate. However, we
found that Zn-free ethylmagnesium N-methyl-(−)-ephedrinate and diphenyl
sulfoxide (16) provided racemic ethyl phenyl sulfoxide (9a) in 68% yield
(THF, −40°C, 20 h). Chemically, this transformation equals the transfor-
mation described by entry 3 of Table 2 except that no ZnEt2 was present.
However, in the presence of ZnEt2 the latter transformation gave the same
sulfoxide 9a in 93% yield (−40°C, 20 h) but with 62% ee. This difference
shows that a zinc species is vital for the enantioselectivity which we
observed. Of course, this pair of experiments does not exclude that the
transformation of entry 3 of Table 2 proceeds in parts via a zincate and in
parts via ethylmagnesium N-methyl-(−)-ephedrinate.
[21] The β-aminoalcohols and the diaryl sulfoxides were dissolved in THF. The
dialkylmagnesium reagents were used as solutions in Et2O and the dialkyl-
zinc reagents as solutions in n-hexane. As a result, our sulfinylations were
performed in mixtures of THF, Et2O, and n-hexane wherein THF repre-
sented the major component.
[22] While the reaction proceeds much faster at elevated temperatures, we ob-
served that the enantiomeric excess was much lower. So, for all following
reactions we searched for the lowest reaction temperature possible in order
to maximize the enantioselectivity.
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[11] Neglecting the (indispensable activating) effect of the cyano group in the
sulfoxide 8, the overall process sulfoxide 8 + nBuEt2Zn⊖ ⊕Li → sulfoxide
9a + Zn-containing compound 10 of Scheme 1 examplifies a transformation
Ar−S(=O)−Ar + Alk−M → Ar−S*(=O)−Alk + Ar−M. The latter represents
1)
a sulfinylation of Alk−M or a metal/sulfoxide exchange in the
organometallic substrate (these view-points are the same except for the
phrasing; they equal the perspective of the present manuscript which, in
addition, sticks to the first phrasing throughout); 2) a sulfoxide/metal ex-
change in the starting sulfoxide; and thereby 3) a desymmetrization of the
starting sulfoxide. In accordance with these deliberations, this manuscript
refers to the project idea 11 → 12 + 13 (Scheme 1) and its many
substantiations (Tables 2-5, Scheme 2) neither as zinc/sulfoxide nor as
sulfoxide/zinc exchange reactions but as organozincate sulfinylations.
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12
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10.1002/ejoc.201701603
European Journal of Organic Chemistry
FULL PAPER
deprotonated with 2.0 equiv. of Alkyl2Mg in THF at room temperature. After
30 min 1.0 equiv. of Alkyl2Zn was added. After another 10 min, this solution
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pyl-(−)-ephedrine (30), N,N-dibutyl-(−)-norephedrine (31), N,N-dibenzyl-
(−)-norephedrine (32), N,N-bis[(4-methoxyphenyl)methyl]-(−)-norephe-
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was added dropwise to
sulfoxide (50) in THF.
a precooled solution of bis(4-chlorophenyl)
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[44] This method is akin to two methods which we described in ref. [12c] and the
Supporting Information of ref. [12b]. In the former work we exchanged het-
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groups and in the latter work we exchanged 4-chlorophenyl groups in a
number of isocyclic aryl alkyl sulfoxides for biphenyl or p-anisyl groups, re-
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[31] N-Isopropyl-(−)-ephedrine (30) was not prepared from (−)-ephedrine but
from (−)-norephedrine: 1) isopropylation with iPrI; 2) ESCHWEILER-CLARKE
-
methylation (cf. Supporting Information and the literature procedure cited
in ref. [29]).
[32] The zincates used for the study of Scheme 2 were prepared like their Et-
containing antecessor 40: 2.0 equiv. of N-methyl-(−)-ephedrine (18) were
13
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