Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion

Article abstract of DOI:10.1002/chem.201901163

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described_. The CCR generally requires dual Ni catalysis and MgBr₂ promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr₂ in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl₂ as a precatalyst and MgBr₂ with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh₃)₂Cl₂ as a precatalyst and ZnPh₂ does not require salt promotion and is stereoretentive. The reaction with Zn(CH₂SiMe₃)₂, however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh₃)₂Cl₂. Ni-Catalyzed and MgBr₂-promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh₂ and Zn(CH₂SiMe₃)₂ is stereoretentive with Ni(dppp)Cl₂ and Ni(PPh₃)₂Cl₂. CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.

Full text of DOI:10.1002/chem.201901163

A Journal of
Accepted Article
Title: Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl
Aminosulfoxonium Salts by Dual Nickel Catalysis and Lewis Acid
Promotion
Authors: Hans-Joachim Gais
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To be cited as: Chem. Eur. J. 10.1002/chem.201901163
Link to VoR: http://dx.doi.org/10.1002/chem.201901163
Supported by

10.1002/chem.201901163
Chemistry - A European Journal
1
Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl
Aminosulfoxonium Salts With Organozincs by Dual Nickel
Catalysis and Lewis Acid Promotion
Irene Erdelmeier,[a][b] Gerd Bülow,[a][c] Chang-Wan Woo,[a][d] Jürgen Decker,[a][e] Gerhard Raabe,[a] and
Hans-Joachim Gais*[a]
Abstract: In this article we describe the cross-coupling reaction
(CCR) of exocyclic, axially chiral and acyclic alkenyl (N-
methyl)sulfoximines with alkyl- and arylzincs. The CCR generally
requires dual Ni-catalysis and MgBr2 promotion, which is effective in
ether but not in THF. NMR spectroscopy revealed a complexation of
alkenyl sulfoximines by MgBr2 in ether, suggesting an acceleration
of the oxidative addition through nucleofugal activation. The CCR of
alkenyl sulfoximines generally proceeds in the presence of
Ni(dppp)Cl2 as precatalyst and MgBr2 with alkyl- and arylzincs with
a high degree of stereoretention at both the C and S atom. While
CCR of axially chiral alkenyl sulfoximines with Ni(PPh3)2Cl2 as
precatalyst and ZnPh2 requires no salt promotion and is
stereoretentive, that with Zn(CH2SiMe3)2 demands salt promotion
and is not stereoretentive. CCR of axially chiral α-methylated alkenyl
sulfoximines afforded per-substituted axially chiral alkenes with high
selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive
CCR with Grignard reagents and Ni(PPh3)2Cl2. Ni-Catalyzed and
MgBr2 promoted CCR of (E)-configured acyclic alkenyl sulfoximines
and aminosulfoxonium salts with ZnPh2 and Zn(CH2SiMe3)2 is
stereoretentive with Ni(dppp)Cl2 and Ni(PPh3)2Cl2. CCR of acyclic
alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a
methyl group at the α-position, take a different course and give
alkenyl sulfinamides under stereoretention at the S and C atom.
CCR of acyclic, exocyclic and axially chiral alkenyl sulfoximines has
been successfully applied to the stereoselective synthesis of
homoallylic alcohols, exocyclic alkenes and axially chiral alkenes,
respectively.
conversion of the chiral bicyclic ketone 1 to (E)-configured alkyl-
and aryl-substituted exocyclic alkenes (E)-3 (Scheme 1). This
problem is closely related to that of the enantioselective
synthesis of the axially chiral alkenes (aR)-6 from achiral
cyclohexanone 4.[6−8] Although both ketones are biased towards
the addition of nucleophiles, a chiral reagent or catalyst is
required for their diastereo- and enantioselective olefination. In
order to find a solution for this problem, we and others had
previously studied the Horner-Wadsworth-Emmons reaction of
ketone 1 and structurally related achiral bicyclo[3.3.0]octanones
with chiral lithium phosphonoacetates.[9−11] Although high
diastereoselectivity was observed in the HWE reaction, it
ultimately gave access only to carbonyl-substituted alkenes (E)-
3.[12] The other methods for the enantioselective olefination of 4,
which had been described at the beginning of our studies,[6,7]
were unsuitable for the stereoselective conversion of ketone 1 to
the required alkenes (E)-3. Hence, we envisioned a new general
stereoselective synthesis of alkenes (E)-3 and (aR)-6 by a two-
step route, featuring a conversion of ketones 1 and 4 to the
corresponding alkenyl sulfoximines (E,R)-2 and (aR,R)-5
followed by their transition-metal-catalyzed cross-coupling
reaction (CCR)[13] with organometallics. We had previously
shown that inverse Peterson olefination (IPO) of ketones 1 and 4
with lithiomethyl sulfoximine (R)-Li-7a[14,15] (see Supporting
Information) affords the corresponding alkenyl sulfoximines
(E,R)-2 and (aR,R)-5 with high diastereoselectivity.[16] Running
the IPO of 1 with (S)-Li-7a[14,15] furnished (Z,S)-2 with similar
high stereoselectivity.[16] Thus, the conditions were given for an
investigation of the CCR of alkenyl sulfoximines with
organometallics. Studies of transition-metal-catalyzed alkenyl
C−S CCR are limited compared with alkenyl C−halide and C−O
CCR.[17] Transition-metal-catalyzed CCR of alkenyl sulfoximines
had not been studied. Information about CCR of alkenyl sulfones,
which could have served as model, were scarce[18] and CCR of
alkenyl sulfoxides was unknown. Only the CCR of alkenyl
sulfides had received broader attention.[17,19] Thus, predictions
on the feasibility of a CCR of alkenyl sulfoximines and its
stereochemical course were difficult to make.
Introduction
During synthetic studies of the medicinally important or prom-
ising prostacyclin[1] analogs iloprost,[2] cicaprost[3] and inter-m-
phenylene carbacyclin[4,5] we encountered
a
challenging
stereochemical problem, namely the diastereoselective
The study of the CCR of the alkenyl sulfoximines (E,R)-2 and
(aR,R)-5 was extended to that of the acyclic alkenyl sulfoximines
(E)-8, which are available through reaction of sulfonimidoyl-
substituted bis(allyl)titaniums with aldehydes (Figure 1).[20] The
purpose of the inclusion of (E)-8 was twofold. First of all, it was
of interest to define the scope and limitation of the CCR of
alkenyl sulfoximines by also studying acyclic substrates, and
second, it seemed desirable to enhance the synthetic potential
of (E)-8[21] through conversion to the substituted homoallylic
alcohols (E)-9, which are a valuable starting material in natural
product synthesis.[22] Included into the study of the CCR of the
acyclic alkenyl sulfoximines were the corresponding
[a]
Prof. Dr. H.-J. Gais, Dr. I. Erdelmeier, Dr. G. Bülow, Dr. C.-W. Woo,
Dr. J. Decker, Prof. Dr. G. Raabe
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
E-mail: gais@rwth-aachen.de
Dr. I. Erdelmeier,
Innoverda, 38 Rue Dunois, 75013 Paris (France)
Dr. G. Bülow
Kurze Maräcker 1, 67133 Maxdorf/Pfaltz (Germany)
Dr. C.-W. Woo
Drosselweg 56, 41189 Mönchengladbach (Germany)
Dr. J. Decker
[b]
[c]
[d]
[e]
Salierstrasse 30, 67373 Dudenhofen (Germany)
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901163
Chemistry - A European Journal
2
aminosulfoxonium salts (E)-10, which are readily accessible
through methylation[23] of (E)-8.[21a,24] Alkenyl aminosulfoxonium
salts are perhaps more reactive in CCR than alkenyl
sulfoximines, because of the higher nucleofugacity of the
cationic aminosulfoxonium group.[21a,24] While a few examples of
transition metal-catalyzed CCR of alkenyl sulfonium salts had
been described,[25,26] nothing was known about the CCR of
alkenyl aminosulfoxonium salts.
H
CO2
H
CO2
H
CO2
H
H
H
H
H
H
O
H
O
H
O
H
O
H
H
H
e
M
e
M
e
M
H
O
H
O
H
O
-
-
e
M
c ca ros
t
o ros
il p
n er m en ene car ac c n
e
M
t
i
p
i t
ph yl
b
y li
Ph
O
rev ous wor
k
w r
o
k
s
Thi
P
i
H
H
H
R
e
NM
S
P
P
GO
GO
O
P
GO
H
H
H
H
E R
H
P
GO
P
GO
P
GO
-
-
,
IP
O
R
Z R2
CC
n
2
E 3
( )
1
(
)
,
Ph
O
,
Ni 0 Ln
( )
Li
S
e
r
NM
M B
g
Ph
2
-
-
O
a
7
R Li
(
)
e
NM
S
R
H
u
u
u
tB
O
tB
tB
H
-
,
-
a
5
)
a
R R
4
R 6
(
(
)
Scheme 1. Stereoselective synthesis of exocyclic and axially chiral alkenes through IPO of cycloalkanones and CCR of alkenyl sulfoximines (PG = protecting
group).
rev ous wor
k
P
i
alkenyl aminosulfoxonium salts with organozincs. It is shown
that the CCR generally proceeds through a dual Ni-catalysis and
magnesium bromide promotion. The CCR has been successfully
applied to the stereoselective synthesis of alkyl- and aryl-
substituted exocyclic, axially chiral and acyclic alkenes of the
type depicted in Scheme 1 and Figure 1.[27]
Ph
O
R
O
Ph
O
R1
H
C O
S
R2
S
R1
e
NM
e
NM
2
-
R2
E
(
8
)
Ti R
O
( )
2
w r
o
s
Thi
k
Ph
O
-
Results and Discussion
R
O
R
O
S
S
R3
R1
R1
e
NM
CCR of alkenyl sulfoximines
R
R
CC
R2
n
-
,
3
R2
Z
Organolithiums and Grignard reagents metalate alkenyl
sulfoximines (E,R)-2, (aR,R)-5 and (E)-8, affording the
corresponding α-metalloalkenyl sulfoximines (E,R)-M-2, (aR,R)-
M-5 and (E)-M-8. The metalloalkenyl sulfoximines are
configurationally labile[21,27a,28,29] and engage in a Ni-catalyzed
anionic CCR (ACCR) with RLi and RMgX to yield α-
alkenylmetals (E/Z)-M-3, (aS)-M-6 and (E/Z)-M-9.[27a,29] These
observations precluded the application of RLi and RMgX in Ni-
catalyzed CCR of the alkenyl sulfoximines and suggested the
use of organozincs,[30] which are not capable to metalate alkenyl
(
)
2
E
8
E
9
)
(
)
(
,
Ni 0 Ln
( )
r
M B
g
Ph
2
O
R
O
R
O
R3
e
R1
NM
R1
2
R2
R2
BF4
-
-
10
)
E
9
)
E
(
(
Figure 1. Stereoselective synthesis of homoallylic alcohols through CCR of
acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts.
sulfoximines.
We
employed
ZnMe2,
ZnPh2,
Zn(m-
C6H4CH2OSitBuMe2)2 (12), Zn[(CH2)4OSitBuPh2]2 (14),
Zn(CH2SiMe2OiPr)2 (21) and Zn(CH2SiMe3)2 (22) as
In this paper we describe the results of an extended
investigation of the nickel-CCR of alkenyl sulfoximines and
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10.1002/chem.201901163
Chemistry - A European Journal
3
diorganozincs, because of synthetic (vide infra) and mechanistic
considerations.
conversion of (E,R)-2 to alkene (E)-3a of ≥98:2 dr. Similar
observations were made with ZnBr2 as additive. The addition of
5 equivalents of ZnBr2 resulted in no conversion of the alkenyl
sulfoximine, while a 50% conversion of the alkenyl sulfoximine to
the alkene occurred with 15 equivalents of the salt. All reactions
in the presence of the zinc halides took place under
homogeneous conditions.
Exocyclic alkenyl sulfoximines
The investigation was begun with the exocyclic alkenyl
sulfoximines (E,R)-2 and (Z,S)-2, because of their relevance for
the synthesis of the prostacyclin analogs. A prime goal was the
CCR of (E,R)-2 with organozincs 12, 14 and 21 under formation
of the corresponding alkenes (E,R)-3a−c.
Finally, the Ni-catalyzed CCR of the isomeric alkenyl sulfoximine
(Z,S)-2 was investigated. It was expected that the remote
stereogenic centers of the other five-membered ring would exert
only a minor effect upon the stereochemistry of the CCR.
Treatment of (Z,S)-2 of 96:4 dr with ZnPh2/2MgBrCl (4 equiv)
and Ni(dppp)Cl2 (5 mol%) in ether at reflux afforded alkene (Z)-
3a in 81% yield and 92:8 dr.
R
O
Ph
O
H
H
e
NM
S
12
Ni dppp
(
R
O
R
O
l
C
)
2
H
H
H
H
R
O
r
er
R
O
M B
l
g
th
C
-
-
,
e
2
)
E R
E 3b
(
(
)
,
∆
T 20 h
R
O
R
O
n
n
Z
Z
l
C 2
r
r
B M
g
M B
g
l
C
2
=
Scheme 2. CCR of exocyclic alkenyl sulfoximines (E,R)-2 and (Z,S)-2 with
ZnPh2.
u
e
12
R
itB M
S
11
2
Scheme 3. CCR of exocyclic alkenyl sulfoximine (E,R)-2 with diarylzinc 12.
Exploratory experiments were carried out with ZnPh2. Treatment
of (E,R)-2 with ZnPh2 (5 equiv) and Ni(dppp)Cl2 (5 mol%) (dppp
= 1,3-bis(diphenylphosphino)propane) as precatalyst in ether
even for a prolonged period of time saw no conversion of the
alkenyl sulfoximine (Scheme 2). Surprisingly, running a similar
experiment with (E,R)-2 (≥98:2 dr) and Ni(dppp)Cl2 (5 mol%) by
using ZnPh2 (4 equiv), which had been prepared in situ from
ZnCl2 and PhMgBr, resulted in a complete conversion of the
substrate and gave alkene (E)-3a in 83% and ≥98:2 dr.
Apparently, the presence of the salt MgBrCl in the second
experiment had made the difference and caused a promotion of
the CCR. Therefore, a third experiment was carried out with
(E,R)-2 and Ni(dppp)Cl2 in ether except that ZnPh2 (5 equiv)
was used together with MgBr2/Et2O (2.5 equiv) as additive.
Thereby, alkene (E)-3a was obtained in 85% yield and ≥98:2 dr.
The configuration of the alkene was determined by NOE
experiments. These findings showed that the Ni-catalyzed CCR
of the alkenyl sulfoximine with ZnPh2 requires a promotion by a
magnesium salt. Both CCRs took place under homogenous
reaction conditions. After the addition of ZnPh2 and MgBr2 or
ZnPh2/2MgBrCl to (E,R)-2 and Ni(dppp)Cl2 in ether, the red
crystals of the Ni-complex slowly dissolved and a yellow solution
of the Ni(0)-catalyst was formed. In order to find out whether the
rate acceleration of the Ni-catalyzed CCR of (E,R)-2 with ZnPh2
is specifically caused by magnesium salts, experiments were
run with zinc halides. While no Ni-catalyzed CCR of (E,R)-2 with
ZnPh2 (5 equiv) occurred in the presence of 5 equivalents of
ZnCl2, the addition of 10 equivalents of ZnCl2 gave a 50%
The synthesis of inter-m-phenylene carbacyclin (cf. Scheme 1)
from alkenyl sulfoximine (E,R)-2 demanded as key step a CCR
of the later with the functionalized diarylzinc 12 (Scheme 3). The
salt-containing diarylzinc was prepared from Grignard reagent
11 and ZnCl2.[31] Treatment of (E,R)-2 with 12/2MgBrCl (2.5
equiv) and Ni(dppp)Cl2 (5 mol%) in ether at reflux afforded
alkene (E)-3b in 89% yield and ≥98:2 dr.
Ph
O
´
H
H
R
C
2 4O
H
14
Ni dppp
(
(
)
e
NM
S
H
l
2
R
C
)
O
R
O
r
M B
g
2
H
H
R
O
H
e
er
,
R
O
th
-
-
-
,
ο
c
3
+
E
2
16
E R
R
/S
(
)
(
)
(
)
0 C 5 d
.
,
n
1 Z Cl2
e
´
,
er
∆
´
th
T
R
O
R
O
n
Z
lM
C
g
2
.
-
n
exane
14
2
h
13
r
M B
g
l
↓
=
C
´
,
=
u
e
u
R
itB M
R
itB Ph
S
S
2
2
Scheme 4. CCR of exocyclic alkenyl sulfoximine (E,R)-2 with dialkylzinc 14.
The synthesis of iloprost (cf. Scheme 1) from alkenyl sulfoximine
(E,R)-2 asked for a CCR of the later with the functionalized
dialkylzinc 14 (Scheme 4). The salt-free dialkylzinc was
This article is protected by copyright. All rights reserved.

10.1002/chem.201901163
Chemistry - A European Journal
4
synthesized from Grignard reagent 13 and ZnCl2.[31] Treatment
of (E,R)-2 with 14 (3.4 equiv), Ni(dppp)Cl2 (5 mol%) and
MgBr2/Et2O (6.8 equiv) in ether at 0 °C afforded alkene (E)-3c in
65% yield and 98:2 dr. The configuration of the alkene was
determined by NOE experiments. Surprisingly, in addition to the
alkene a mixture of the diastereomeric alkyl sulfoximines (R)-16
and (S)-16 (Scheme 5) was isolated in 20% yield and 87:13 dr.
substituted allylic silane (E)-3d can be oxidized to the allylic
alcohol (E)-3e.[34] Treatment of (E,R)-2 of 99.5:0.5 dr with 21 (2
equiv), Ni(dppp)Cl2 (20 mol%) and MgBr2/Et2O afforded the
allylic silane (E)-3d in 92% yield and 98.5:1.5 dr. The
configuration of the alkene was secured by NOE experiments. A
similar CCR of the isomeric alkenyl sulfoximine (Z,S)-2 of
96.4:3.6 dr with 21 furnished the isomeric alkene (Z)-3d in 92%
yield and 95.5:4.5 dr.
´
Ph
e
Hydronickelation: formation of alkyl sulfoximines (R)-16 and (S)-
16 in the reaction of (E,R)-2 with dialkylzinc 14 in the presence
of Ni(dppp)Cl2 and MgBr2 revealed a competition between
hydronickelation and CCR of the alkenyl sulfoximine. Because of
the promotion of the CCR by the salt, it was of interest to see
whether hydronickelation[32] would be the exclusive path-way
when CCR would be shut down by omitting the salt.
iM
R
2O
S
O
21
Ni dppp
(
H
H
e
NM
S
l
2
C
)
R
O
R
O
r
M B
g
th
2
,
,
H
e
er r
t 1 d
H
H
R
O
H
R
O
-
-
,
E 3d
2
E R
(
)
(
)
H
H
Ph
H
S
H
21
Ni dppp
O
R
O
R
O
l
C
)
(
2
H
H
H
e
NM
O
S
H
e
NM
H
Ph
e
r
g
M B
H
H
14
Ni dppp
(
R
O
2
R
O
`
R
O
R
O
,
,
S
e
iM R
2O
-
e
er r
th
S
-
t 1 d
,
O
Ph
l
C
)
Z 3d
( )
2
2
Z
S
(
)
NM
H
R
O
R
O
e
th
er
X
n
-
,
,
2
)
E R
∆
T 1 d
,
(
-
-
-
-
´
n r
Z B THF
,
,
=
=
:
15
16
2
15
16
R
R
( )
X
X
Z
H R
2 4O
)
S
S
( )
C
(
( )
( )
r
r
M B
g
n
Z
B M
Ph
g
O
Ph
2
O
:
2
H
19
18
´
=
´
,
=
=
+
17
H
C
H H R
C C 2 2O
( )
u
e
u
(
)
R
itB M
R
itB Ph
S
2
S
2
2
.
,
n
-
1 Z
l
THF
C 2
e
r
n
Z
e
r
iP
2O
lM
iM
S
iP
2O
C
g
iM
S
2
.
Scheme 5. Ni-catalyzed hydronickelation of exocyclic alkenyl sulfoximine
(E,R)-2 with dialkylzinc 14.
n
exane
2
h
20
21
M
l
↓
till ti
gC 2
.
s
3 di
a on
Treatment of (E,R)-2 with dialkylzinc 14 and Ni(dppp)Cl2 (8
mol%) without MgBr2/Et2O at reflux gave after aqueous work-up
a mixture of the alkyl sulfoximines (R)-16 and (S)-16 in 73%
yield and 87:13 dr. In addition to the alkyl sulfoximines, butene
17 was formed to a similar extend. Without the Ni-precatalyst
formation of the alkyl sulfoximines was not observed and only
trace amounts of alkene (E)-3c were detected. HPLC furnished
the pure major diastereomer (R)-16, the configuration of which
was ascertained by NOE experiments. Formation of (R)-16 and
(S)-16 most likely involves a hydronickelation of (E,R)-2 followed
by a Ni-Zn-exchange and protonation of thus generated alkylzinc
sulfoximine (R)-15 and (S)-15 (see Scheme S8, Supporting
Information).
Scheme 6. CCR of exocyclic alkenyl sulfoximines (E,R)-2 and (Z,S)-2 with
bis(silylmethyl)zinc 21.
Surprisingly, CCR of (E,R)-2 with 21 in ether in the presence of
MgBr2 and Ni(PPh3)2Cl2 as precatalyst was unselective and
slow, furnishing a mixture of (E)-3d and (Z)-3d in 59:41 dr and
only 21% yield. The alkenyl sulfoximine of unchanged dr was
recovered in 62% yield.
e
iM
R
2O
S
H
H
H
O
,
H
KH
e
2O2
CO3
R
O
R
O
,
,
∆
THF M
H
O
T
H
H
-
H
R
O
H
R
O
-
e
3
E
(
E
3d
)
)
(
The synthesis of cicaprost (cf. Scheme 1) from alkenyl
sulfoximine (E,R)-2 required as key step a conversion of the
latter to the allylic alcohol (E)-3e (Scheme 7). Therefore, we
planned a CCR of (E,R)-2 with bis(benzyloxymethyl)zinc 19
(Scheme 6), which was prepared from Grignard reagent 18 and
ZnBr2 in THF.[33] However, despite several attempts a Ni-
catalyzed CCR of (E,R)-2 with 19/MgBrCl could not be achieved.
As an alternative, a step-wise introduction of the hydroxymethyl
group of (E)-3e was envisioned,[34] using bis(alkoxysilylmethyl)-
zinc 21, which was synthesized salt-free from Grignard reagent
20 and ZnCl2.[35] Organozinc 21 is structurally remarkable since
it features in the crystal a coordination of the Zn atom by the two
C atoms and the O atom of a second molecule in a trigonal
planar fashion.[35] It was to be expected that the alkoxy-
H
H
H
H
,
H
KH
e
2O2
CO3
RO
R
O
,
,
∆
T
THF M
`
H
O
H
O
H
H
-
R
O
R
O
-
e
R
2O
iM
S
e
3
Z
( )
Z
3d
( )
u
tB
CO2
H
O
r
u
R
O
B
H
tB
2CO2
C
-
e
3
E
(
)
H
H
-
R
O
E
(
3g
)
´
,
=
=
u
e
r
R
itB M
R
iP
S
2
Scheme 7. Oxidation of exocyclic allylic silanes (E)-3d and (Z)-3d.
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10.1002/chem.201901163
Chemistry - A European Journal
5
Oxidation of the allylic silanes (E)-3d and (Z)-3d with hydrogen
peroxide[34] and purification by HPLC gave the corresponding
allylic alcohols (E)-3e of ≥99:1 dr and (Z)-3e of ≥99:1 dr in 69%
yield and 64% yield, respectively. Alkylation of the allylic alcohol
(E)-3e with tert-butyl bromoacetate gave ether (E)-3g.
The CCR of the diastereomeric axially chiral alkenyl
sulfoximines (aS,S)-5a and (aR,S)-5a with alkyl- and arylzincs
was studied in more detail under variation of precatalyst, salt
additive and solvent. The axially chiral alkenyl sulfoximines have
in contrast to the alkenyl sulfoximines (E,R)-2, (Z,S)-2 and (E)-8
a stereochemically unbiased carbon skeleton, which should
make them useful probes for the stereochemistry of the CCR. In
addition, the availability of both diastereomeric alkenyl
sulfoximines will allow the determination of the influence of the
configuration of the sulfonimidoyl group upon the CCR.
The facile synthesis of the allylic silanes (E)-3d and (Z)-3d led
us to explore the CCR of (E,R)-2 with bis(silylmethyl)zinc 22[36] in
order to see whether allylic silanes, carrying no functional
groups at the Si atom, can also be obtained. CCR of (E,R)-2 of
99.5:0.5 dr with salt-free 22 (3 equiv) and Ni(dppp)Cl2 (10 mol%)
in the presence of MgBr2/Et2O (3 equiv) furnished the allylic
silane (E)-3f in 87% yield and 99.5:0.5 dr (Scheme 8). CCR by
using MgI2 as additive gave similar results but the reaction
proceeded to completion in much shorter time (two days versus
five days).
Diphenylzinc and Ni(dppp)Cl2: treatment of
a mixture of
Ni(dppp)Cl2 (10 mol%), MgBr2/Et2O (3 equiv) and salt-free
ZnPh2 (3 equiv) in ether with (aS,S)-5a following an induction
period of 15 min (mode A) afforded alkene (aS)-6a in 72% yield
and 92:8 er (Table 1, entry 1) (Scheme 9). A similar treatment of
a mixture of Ni(dppp)Cl2 (10 mol%), MgBr2/Et2O (3 equiv) and
ZnPh2 (3 equiv) with diastereomer (aR,S)-5a (mode A) in ether
furnished the enantiomeric alkene (aR)-6a in 72% yield and 96:4
er (entry 2).
Ph
O
22
Ni dppp
(
H
H
e
NM
S
H
e
iM
S
3
l
2
C
)
R
O
R
O
r
M B M I
g
th
g 2
(
t
)
2
,
H
H
e
er r
H
H
n
R
O
R
Z Ph2
O
H
-
-
H
,
5 d 2 d
(
)
E
3f
2
E R
(
Ni dppp
(
l
2
C
(
)
)
)
u
tB
u
tB
r
M B
g
2
Ph
e
,
,
NM
Ph
S
H
H
e
er r
th
mo e
d
t
h
6
-
-
H
S
,
a
a
a
5
a
22
Ni dppp
(
6
S
)
S S
(
(
)
A
O
O
R
O
R
O
l
2
C
)
e
iM
S
,
e
NM
3
e
er
M I
g 2
th
H
H
-
R
O
R
O
,
Ph
NM
O
r
t 4 d
-
,
Ph
Z
3f
2
Z
(
S
n
( )
)
Z Ph2
Ph
H
e
S
n
Z
C
(
e
H iM
2S
22
)
Ni dppp
(
l
C
)
3 2
(
)
2
u
tB
u
tB
r
M B
g
2
,
,
H
e
th
er r
mo e
d
t 1
8
h
-
Scheme 8. CCR of exocyclic alkenyl sulfoximines (E,R)-2 and (Z,S)-2 with
bis(silylmethyl)zinc 22.
-
,
a
R 6
)
a
a
5
a
R
S
(
(
)
A
H
u
tB
CCR of the diastereomeric alkenyl sulfoximine (Z,S)-2 of
96.4:3.6 dr with salt-free 22 (3 equiv) and Ni(dppp)Cl2 (10 mol%)
in the presence of MgI2 (3 equiv) gave the allylic silane (Z)-3f in
40% yield and 91.1:8.9 dr. Alkenyl sulfoximine of unchanged dr
was recovered in 38% yield.
Because of the many useful synthetic transformations allylic
silanes can undergo,[22a,b] (E)-3f should be an interesting building
block for the synthesis of prostacyclin analogs, carrying a side-
chain at a di-substituted ring C atom.
u
tB
H
23
Scheme 9. Ni-catalyzed CCR of axially chiral alkenyl sulfoximines (aS,S)-5a
and (aR,S)-5a with ZnPh2.
The er of (aR)-6a and (aS)-6a was determined by 1H NMR
spectroscopy in the presence of Agfod/Pr(tfc)3
[37]
(fod = 7,7-
CCR of (E,R)-2 with 22 in the presence of MgBr2 or MgI2 by
using Ni(PPh3)2Cl2 (10 mol%) was slower and gave a mixture of
the allylic silanes (E)-3f and (Z)-3f in only 39% yield and 66:34
dr. The alkenyl sulfoximine of unchanged dr was recovered in
35% yield.
dimethyl-1,1,1,2,2,3,3-heptafluoro-octan-4,6-dionato; tfc = (3-
trifluoroacetyl-d-camphorato) and by GC on a chiral stationary
phase. The absolute configuration of (aS)-6a was assigned
based on a comparison of its chirotropic properties with those
reported in the literature.[7e]
In summary, CCR of (E,R)-2 with bis(silylmethyl)zincs 21 and 22
by using monophosphine precatalyst Ni(PPh3)2Cl2 were not
only slower than those with bisphosphine precatalyst
Ni(dppp)Cl2 but also proceeded with a low degree of stereo-
retention.
Diphenylzinc and Ni(PPh3)2Cl2: substitution of Ni(dppp)Cl2 by
Ni(PPh3)2Cl2 in the CCR of (aR,S)-5a and (aS,S)-5a and
omitting the induction period (mode B) gave the corresponding
alkenes in similar yields and er (entries 3 and 4). With
Ni(PPh3)2Cl2 as pre-catalyst CCR of (aS,S)-5a was faster than
with Ni(dppp)Cl2. The fastest CCR of (aS,S)-5a with ZnPh2 in
the presence of MgBr2/Et2O in ether was observed by using a
Ni-catalyst, presumably Ni(PPh3)4,[38a] which was prepared from
Axially chiral alkenyl sulfoximines
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10.1002/chem.201901163
Chemistry - A European Journal
6
Ni(PPh3)2Cl2 and MeLi in the presence of PPh3 (entry 5).[38b,c]
Thereby, alkene (aS)-6a was obtained in 61% yield and 97:3 er
after a reaction time of only 0.5 h. The use of Ni(PPh3)2Cl2 in
CCR of (aR,S)-5a with ZnPh2 was accompanied by a homo-
coupling of the alkenyl sulfoximine and gave (aR)-6a and diene
23 (mixture of diastereomers) in a ratio of 82:18 (entry 4).
Surprisingly, the alkenyl sulfoximine (aR,S)-5a also engaged in
the absence of MgBr2/Et2O according to mode B in an efficient
and highly selective CCR with ZnPh2 and the monophosphine
precatalyst Ni(PPh3)2Cl2 in ether (entry 6). Similarly, the CCR of
the diastereomeric alkenyl sulfoximine (aS,S)-5a also gave in
the absence of MgBr2 with Ni(PPh3)2Cl2 in ether (mode B)
alkene (aS)-6a in 97:3 er (entry 7). However, because of the
competing conjugate addition (vide infra), the chemical yield of
the alkene was only 29%. The CCR of (aR,S)-5a with ZnPh2
and Ni(dppp)Cl2 in ether was in the absence of MgBr2/Et2O
slow and of low selectivity (mode B) (entry 8).
[a,b]
Table 1. Ni-catalyzed CCR of alkenyl sulfoximines (aS,S)-5a and (aR,S)-5a with salt-free ZnPh2
.
entry
sulfoximine
mode
precatalyst/
catalyst
salt
solvent
t (h)
6a,
yield (%)
(aS)-6a:(aR)-6a
5, 6, 23, (cis,S)-24
1
(aS,S)-5a
(aR,S)-5a
(aS,S)-5a
(aR,S)-5a
(aS,S)-5a
(aR,S)-5a
(aS,S)-5a
(aR,S)-5a
(aS,S)-5a
(aR,S)-5a
(aS,S)-5a
(aR,S)-5a
A
A
B
B
B
B
B
B
B
B
B
B
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
-
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
6
72
72
65
67
61
92:8
4:96
98:2
8:92
97:3
3:97
97:3
-
2
18
2
-
3
(cis,S)-24:(aS)-6a = 13:87
(aR)-6a:23 = 82:18.
-
4
24
0.5
24
24
72
24
24
24
24
[e]
5
Ni(PPh3)4
6
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
71
(aR,S)-5a:(aR)-6a = 5:95
(cis,S)-24:(aS)-6a:(aS,S)-5a=65:29:6
(aR,S)-5a:(aR)-6a = 55:45
(cis,S)-24:(aS)-6a:(aS,S)-5a=76:9:15
(aR,S)-5a:(aS)-6a = 76:24
(cis,S)-24:(aS)-6a = 20:80
-
[c]
7
-
[c]
[c]
8
-
30:70
[d]
9
MgBr2
MgBr2
MgBr2
MgBr2
10
11
12
THF
15
67
87
67:33
92:8
5:95
Et2O
Et2O
[a] 0.1 mmol 5a, 10 mol% precatalyst or catalyst, 3 equiv of ZnPh2 and with or without 3 equiv of MgBr2. [b] Mode A: after the mixture of ZnPh2, Ni(dppp)Cl2
and MgBr2 in Et2O or THF was kept for 15 min at room temperature, 5a in Et2O or THF was added and the mixture was stirred at room temperature for the
time given. Mode B: a mixture prepared through the successive addition of ZnPh2, Ni(dppp)Cl2, MgBr2 and 5a was stirred in Et2O or THF at rt for the time
given. [c] Not isolated. [d] Not determined. [e] Prepared from Ni(PPh3)2Cl2, PPh3 (2 equiv) and MeLi (2 equiv) in ether.
Conjugate addition: treatment of a mixture of Ni(dppp)Cl2,
Scheme 10. Ni-Catalyzed conjugate addition of ZnPh2 to alkenyl sulfoximine
(aS,S)-5a.
MgBr2/Et2O and salt-free ZnPh2 in ether with alkenyl
sulfoximine (aS,S)-5a without induction period (mode B)
furnished a mixture of alkene (aR)-6a and the phenyl-substituted
alkyl sulfoximine (cis,S)-24 in a ratio of 80:20 (entry 11)
(Scheme 10). Alkene (aS)-6a was isolated in 67% yield and 92:8
Formation of (cis,S)-24 also occurred with Ni(PPh3)2Cl2 in ether
or with Ni(dppp)Cl2 in THF as solvent according to mode B
(entries 3 and 9). The alkyl sulfoximine (cis,S)-24 was formed as
single diastereomer and its configuration was determined by X-
er
H
n
Z Ph2
H
S
u
tB
Ni dppp
(
l
2
C
)
u
tB
ray
crystal
structure
analysis
(see
Supporting
Ph
r
M B
-
g
2
Information).[39] From this result follows that ZnPh2 had
undergone in addition to CCR a diastereoselective Ni-catalyzed
conjugate addition to the alkenyl sulfoximine (aS,S)-5a.
Formation of (cis,S)-24 indicates a selective equatorial CC-bond
formation in accordance with observations made previously in
cuprate reactions of (4-tert-butyl)cyclohexylidene derivatives.[40]
The different results gained in the reactions of (aS,S)-5a
according to modes A and B suggest that in the former case,
because of the induction period, most of the Ni(II)-complex had
been reduced to the Ni(0)-complex before addition of the alkenyl
sulfoximine, while in the latter case both Ni(II)- and Ni(0)-
a
a
6
)
S
e
NM
,
,
(
-
e
er r
,
th
mo e
t 1 d
a
a
5
)
S S
(
+
d
B
O
Ph
-
,
c s
i
24
S
(
)
n
Z Ph2
Ph
O
Ni dppp
(
th
l
2
C
-
)
,
u
tB
a
5
a
S S
(
)
, ,
Ph
e
er r
t 2 h
S
α
e
NM
-
,
c s
i
24
)
S
(
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10.1002/chem.201901163
Chemistry - A European Journal
7
complexes were present. The Ni(0)-complex catalyzed the CCR,
while the Ni(II)-complex catalyzed the conjugate addition.[41] In
order to collect further support for this scenario, conjugate
addition of ZnPh2 to alkenyl sulfoximine (aS,S)-5a was probed
with catalytic amounts of Ni(II) compounds in the absence of
MgBr2 (Table 2), since CCR of (aS,S)-5a in the absence of the
salt is slow. Reactions were carried out by addition of ZnPh2 to a
mixture of (aS,S)-5a and the Ni-precatalyst (mode C). While with
complexes Ni(dppp)Cl2 and Ni(PPh3)2Cl2 in ether and THF
conjugate addition is the major and CCR the minor path-way
(entries 1−3), with Ni(acac)2 and NiCl2 conjugate addition is
almost the exclusive path-way (entries 4 and 5). Quenching of
the reaction mixtures obtained in conjugate addition with
CF3CO2D gave the deuteriated alkyl sulfoximine (cis,S)-D-24,
containing 89% D at the α-position, in 77% yield and ≥98:2 dr.
In the absence of a nickel compound conjugate addition
occurred only to a minor extent (entries 6−8)
alkenes, which are otherwise difficult to obtain.[6,7] Treatment of
alkenyl sulfoximine (aS,S)-Me-5a (96:4 dr) with salt-free ZnPh2
(3 equiv) in ether with Ni(dppp)Cl2 (10 mol%) without
MgBr2/Et2O furnished alkene (aS)-6c in 82% yield and 96:4 er
(Scheme 12). Surprisingly, the CCR in the presence of
MgBr2/Et2O was slower but gave similar results. The er of (aS)-
1
6c was determined by H NMR spectroscopy in the presence of
[37]
Agfod/Pr(tfc)3
and GC on a cyclodextrin phase and the
absolute configuration assigned based on comparison of its
chirotropic properties with those of alkene (aS)-6a.
n
Z Ph2
e
M
e
M
Ni dppp
(
l
C
)
2
u
tB
u
tB
,
e
er
th
e
NM
S
,
Ph
r
t 1 d
O
-
-
-
,
c
a
S
a
e
5
a
6
)
M
)
S S
(
Ph
(
Scheme 12. CCR of the trisubstituted alkenyl sulfoximine (aS,S)-Me-5a.
Table 2. Conjugate addition of ZnPh2 to alkenyl sulfoximine (aS,S)-5a at
room temperature in the presence of additives
Because of the lack of a α-H atom, CCR of alkenyl sulfoximine
(aS,S)-Me-5a with PhMgBr should be possible. Indeed,
treatment of (aS,S)-Me-5a with Ni(dppp)Cl2 and PhMgBr gave
alkene (aS)-6c in 82% yield and 85:15 er.[42]
entry
additive
t
solvent
(aS,S)-5a:
(S)-6a:
(R)-6a
(h)
(cis,S)-24:(S)-6a
[a]
[a]
[c]
1
2
3
Ni(dppp)Cl2
Ni(dppp)Cl2
24
24
1
Et2O
THF
5:82:13[b]
3:88:9
Dimethylzinc: CCR of alkenyl sulfoximines (aR,S)-5a and (aS,S)-
5a with salt-free ZnMe2 (4 equiv), Ni(dppp)Cl2 (4 mol%) and
MgBr2/Et2O (3 equiv) was much slower than with ZnPh2. It
afforded the corresponding alkenes (aR)-6b in 82% yield and
95:5 er and (aS)-6b in 74% yield and 95:5 er (Scheme 13). The
er of the alkenes was determined by GC on a chiral stationary
phase. The absolute configuration of the alkenes was assigned
based on a comparison of the chirotropic properties with those
reported in the literature.[7c] Alkene 26 of unknown configuration
was isolated as a side product in 2−4% yield.
[c]
[a
Ni(PPh3)2Cl2
Et2O
6:65:29
97:3
]
[d]
[c]
[c]
4
5
6
7
8
Ni(acac)2
1
Et2O
Et2O
Et2O
Et2O
THF
2:95:2
[d]
NiCl2
1h
48
48
48
2:95:2
[d]
MgBr2
88:12:0
83:17:0
100:0:0
-
-
-
[e]
-
Ph
O
e
M
[e]
e
Z M
NM
n
S
e
-
2
u
tB
u
tB
Ni dppp
l
C
)
(
2
[a] To a mixture of alkenyl sulfoximine (aS,S)-5a (.0.10 mmol) and the Ni
compound (10 mol%) was added ZnPh2 (3 equiv) (mode C). [b]
Sulfoximine (cis,S)-24 was isolated in 77% yield. [c] Not determined. [d]
To a mixture of (aS,S)-5a (0.05 mmol) and the Ni compound or salt (10
mol%) was added ZnPh2 (3 equiv). [e] (aS,S)-5a (0.05 mmol) was treated
with ZnPh2 (3 equiv).
H
H
r
MgB
-
,
-
2
a
5
)
a
a
R
)
R S
,
e
r
0
,
°
6b
(
(
e
th
C
5 d
H
S
O
S
H
n
e
2
u
Z M
tB
u
The reactivity of (aS,S)-5a stands in sharp contrast to that of the
diastereomeric alkenyl sulfoximine (aR,S)-5a, which does not
engage in a Ni(II)-catalyzed conjugate addition with ZnPh2
according to modes A−C (Table 1, entries 2 and 12), presumably
because of its faster Ni(0)-catalyzed CCR.
+
tB
Ni dppp
(
l
C
)
e
2
NM
e
)
Ph
N H M
(
e
M
r
MgB
2
-
-
-
-
,
O
a
a
a
S
)
5
S S
6
b
25
H
)
S
(
(
)
(
,
,
°
Ph
e
er
th
5 d
0
C
e
M
u
tB
26
α-Substituted alkenyl sulfoximines: thus far terminal alkenyl
sulfoximines were studied. Lithiation of alkenyl sulfoximines
(E,R)-2, (Z,S)-2 and (aS,S)-5a with MeLi at low temperatures
followed by methylation of the corresponding lithioalkenyl
sulfoximine (E,R)-Li-2, (Z,S)-Li-2 and (aS,S)-Li-5a with MeI in
the presence of HMPA at low temperatures gave the
corresponding methylated alkenyl sulfoximines (E,R)-Me-2,
(Z,S)-Me-2 and (aS,S)-Me-5a in high yield and ≥98:2 dr (see
Supporting Information).[31] This offered the possibility of an
enantioselective synthesis of per-substituted axially chiral
Scheme 13. CCR of alkenyl sulfoximines (aR,S)-5a and (aS,S)-5a with ZnMe2.
In all of the CCRs described above the corresponding metallo
sulfinamides (S)-M-25 and (R)-M-25 were formed in addition to
the alkenes. In the case of the CCR of (aS,S)-5a sulfinamide
(S)-H-25 was isolated, which was obtained in 89% yield and
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10.1002/chem.201901163
Chemistry - A European Journal
8
≥98:2 er. Thus, the CCR of the alkenyl sulfoximine had occurred
with retention of configuration of the chiral axis and S atom.
Conversion of sulfinamide (S)-H-25 into sulfoximine (S)-H-7a,
the chiral reagent used for the synthesis of (aS,S)-5a, had
CCR of the diastereomeric alkenyl sulfoximine (aS,R)-5a in
ether under similar conditions was much slower. Treatment of
(aS,R)-5a with bis(silylmethy)zinc 22 in the presence of
MgBr2/Et2O in ether by using Ni(dppp)Cl2 afforded the allylic
silane (aS)-6d in only 52% yield and 97:3 er (Table 3, entry 5).
The alkenyl sulfoximine of unchanged dr was recovered in 26%
yield.
Rather long reaction times were required for the complete
conversion of the alkenyl sulfoximines. Therefore, the time
dependency of conversion and alkene formation was determined
in the CCR of alkenyl sulfoximine (aR,R)-5a with 22 in the
presence of MgBr2 with Ni(dppp)Cl2 in ether (see Supporting
Information, Table S1). The results show that reaction rate slows
down more than expected towards the end of the reaction, which
could be due to a catalyst deactivation.
already been described.[43]
22
Ni dppp
(
H
H
l
2
C
)
u
tB
u
tB
r
M B
g
th
2
e
SiM
3
e
NM
,
,
S
e
er r
t 4 d
-
-
,
a
a O
Ph
6d
S
)
a
5
S S
(
(
)
22
H
Ni dppp
(
l
2
C
)
-
u
tB
a
S
6d
)
(
r
M B
g
2
e
NM
S
,
,
e
th
er r
t 4 d
-
,
a
a
S
O
5
)
R
(
Ph
Ni(PPh3)2Cl2 as precatalyst: a further surprising observation
was made in the CCR of the alkenyl sulfoximines by using
Ni(PPh3)2Cl2. Treatment of (aR,R)-5a with bis(silylmethy)zinc 22
in the presence of MgBr2/Et2O and Ni(PPh3)2Cl2 gave the allylic
silane (aS)-6d in 72% yield and 72:28 er (Table 3, entries 6 and
7), while a similar CCR of (aS,R)-5a furnished (aR)-6d in 33%
yield and 53:47 er (entry 8). The CCR of (aR,R)-5a proceeded
with the alleged catalyst Ni(PPh3)4 in a similar manner (entry
Ph
O
22
Ni PPh
(
e
NM
S
l
3 2C 2
)
-
a
S
6d
)
u
tB
(
r
M B
g
th
2
,
,
H
e
er r
t 1d
-
,
a
a
5
R R
(
)
Scheme 14. CCR of alkenyl (N-methyl)sulfoximines (aR,R)-5a and (aS,R)-5a
with bis(silylmethyl)zinc 22.
[38d]
11), while no CCR occurred with alleged complex Ni(dppp)2
(entry 12), which was prepared from Ni(dppp)Cl2, dppp (1 equiv)
and MeLi (2 equiv) in ether.[38b,c] Thus, CCR of both alkenyl
sulfoximines took place under inversion of the configuration of
the chiral axis in the presence of PPh3 as ligand for the Ni atom.
Bis(silylmethyl)zincs: the CCR of alkenyl sulfoximines (aS,R)-5a
and (aR,R)-5a with bis(silylmethyl)zincs 21 and 22 was
investigated in order to obtain further information about their
reactivity towards alkylzincs and to explore the synthesis of
functionalized axially chiral alkenes (Schemes 14 and 15, Tables
3 and 4).
Ph
O
´
e
NM
S
H
e
21
Ni dppp
(
iM
S
R
2O
u
tB
u
tB
l
C
)
2
H
H
r
,
MgB
e er
th
2
0
-
-
°
,
,
e
6
a
a
5
)
a
R
R R
4 d
(
)
(
Ni(dppp)Cl2 and salt additive: CCR of (aS,S)-5a with salt-free
bis(silylmethy)zinc 22 (3 equiv) in the presence of MgBr2/Et2O
(3 equiv) in ether by using Ni(dppp)Cl2 (10 mol%) afforded the
allylic silane (aS)-6d in 90% yield and 97:3 er (Table 3, entry 1).
´
=
r
iP
R
H
21
u
tB
Ni dppp
(
l
C
)
2
u
tB
´
e
r
MgB
2
iM
S
R
2O
e
NM
S
1
The er of (aS)-6d was determined by H NMR spectroscopy in
,
,
e er r
th
t 4 d
-
-
,
O
e
6
)
a
S
a
5
)
a
S
R
Ph
(
the presence of Agfod/Pr(tfc)3 and the absolute configuration
(
was assigned based on
a comparison of its chirotropic
properties with those of alkene (aS)-6b.
21
Ni PPh
(
O
S
Next the salt additive (3 equiv) was varied in CCR of (aR,R)-5a
with 22 (1.5 equiv) and Ni(dppp)Cl2 (10 mol%) in ether (Table 4).
MgBr2 and MgI2 caused the highest rate acceleration and LiI
had an intermediate effect (entries 4, 5 and 2). The er of (aR)-6d
was in the case of MgI2 and LiI only 82:18 and 77:23,
respectively (entries 5 and 2). Salts LiBr, LiClO4 and ZnX2 (X =
Cl, Br, I) had only a minor effect upon the rate of the CCR
(entries 1, 3 and 6−8).
l
3 2C 2
)
-
-
,
e
6
a
5
)
a
S
)
a
+
R R
(
(
r
MgB
2
e
)
Ph
N M M
(
°
,
,
-
-
e
th
er
0
C
2 d
25
R
(
M
)
Scheme 15. CCR of alkenyl (N-methyl)sulfoximines (aR,R)-5a and (aS,R)-5a
with bis(silylmethyl)zinc 21.
Interestingly, the amount of MgBr2 used as additive in the CCR
of (aR,R)-5a had a profound influence upon the rate. While with
0.5 equiv no CCR occurred, the use of 1 equiv resulted in the
formation of a mixture of (aR,R)-5a and (aR)-6d in a ratio of
41:59 and the application of 3 equiv gave the alkene in 90%
yield (Table 3, entries 3, 4 and 1).
Interestingly, inversion of configuration was also observed when
Ni(dppp)Cl2 was used in the presence of PPh3 (entry 9). A
similar result was obtained with precatalyst Ni(PPh2Me)2Cl2
(entry 10). Generally, CCRs of the alkenyl sulfoximines with
PPh3 as ligand for the Ni atom were not only less selective but
also faster than those with dppp as ligand. Low selectivity and
inversion of configuration had also been noted in CCR of alkenyl
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10.1002/chem.201901163
Chemistry - A European Journal
9
sulfoximine (E,R)-2 with 22 in the presence of MgBr2 and
Ni(PPh3)2Cl2 (vide supra). These results stand in sharp contrast
to the CCR of (aS,S)-5a and (aR,S)-5a with ZnPh2 where with
Ni(PPh3)2Cl2 a high degree of stereo-retention was found (vide
supra).
Table 3. Ni-catalyzed CCR of alkenyl sulfoximines (aR,R)-5a and (aS,R)-5a with Zn(CH2SiMe3)2 (22)[a]
.
entry
sulfoximine
precatalyst/catalyst
salt
solvent
t (d)
6d, yield (%)
(aR)-6d:(aS)-6d
1
(aR,R)-5a
(aR,R)-5a
(aR,R)-5a
(aR,R)-5a
(aS,R)-5a
(aR,R)-5a
(aR,R)-5a
(aS,R)-5a
(aR,R)-5a
(aR,R)-5a
(aR,R)-5a
(aR,R)-5a
Ni(dppp)Cl2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
Et2O
THF
4
3
2
2
4
1
1
4
2
1
1
1
90
-
97:3
[b]
2
Ni(dppp)Cl2
-
[h]
[i]
3
Ni(dppp)Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
-
-
[j]
[k]
4
Ni(dppp)Cl2
5
Ni(dppp)Cl2
52
72
78
33
86
90
71
-
3:97[c]
28:72[d]
36:64
53:47[e]
28:72
40:60
40:60
-
6
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2/PPh3
Ni(PPh3)2Cl2
Ni(dppp)Cl2/PPh3
Ni(PPh2Me)2Cl2
7
8
9
10
11
12
[f]
Ni(PPh3)4
[g]
Ni(dppp)2
[a] 0.2 mmol 5a, 10 mol% catalyst, 3 equiv of 22 and 3 equiv of salt (mode B). [b] Recovery of 86% (aR,R)-5a. [c] Recovery of 26% (aS,R)-5a. [d] Isolation
of 5% of 22 as a mixture of diastereomers. [e] Recovery of 61% of (aS,R)-5a. [f] Prepared from Ni(PPh3)2Cl2, PPh3 (2 equiv) and MeLi (2 equiv) in ether.
[g] Prepared from Ni(dppp)Cl2, dppp (1 equiv) and MeLi (2 equiv) in ether. [h] 0.5 equiv. [i] 1 equiv. [j] 5a:6d = 41:59. [k] Not determined.
CCR of the alkenyl sulfoximines (aR,R)-5a and (aS,R)-5a with
Table 4. Ni-catalyzed CCR of (aR,R)-5a with Zn(CH2SiMe3)2 (22) in
the presence of salt additives in ether at room temperature[a]
the functionalized bis(silylmethyl)zinc 21 (3 equiv), MgBr2/Et2O
(3 equiv) and Ni(dppp)Cl2 (10 mol%) afforded the corresponding
allylic silanes (aR)-6e in 96% yield and 97:3 er and (aS)-6e in
97% yield and 97:3 er. Again with Ni(PPh3)2Cl2 as precatalyst
inversion of configuration occurred. Besides the alkenes
sulfinamide (R)-H-25 was isolated in 74% yield and ≥98:2 er.
entry
salt
t (d)
(aR,R)-5a:(aR)-6d
(aR)-6d:(aS)-6d
[b]
1
2
3
4
5
6
7
8
LiBr
3
3
3
4
1
3
3
3
98:2
64:36
90:3
5:95
5:95
98:2
98:2
96:4
77:23
LiI
H
KH
2O2
CO3
,
´
H
O
e
iM
S
R
2O
u
tB
[b]
u
tB
LiClO4
MgBr2
MgI2
ZnCl2
ZnBr2
ZnI2
e
H
O
THF M
H
H
∆
T
-
-
a
e
a
R 6f
R 6
97:3
(
)
(
)
´
=
r
iP
R
82:18
Scheme 16. Oxidation of the allylic silanes (aS)-6e and (aR)-6e.
[b]
[b]
[b]
Oxidation of the allylic silanes (aS)-6e and (aR)-6e gave the
corresponding axially chiral allylic alcohols (aS)-6f and (aR)-6f in
75% yield and 73% yield, respectively (Scheme 16). The
absolute configuration of the allylic alcohols was assigned based
on a comparison of its chirotropic properties with those reported
in the literature.[44] Conversion of the allylic alcohols to the
corresponding acetates (aR)-6h and (aS)-6h (see Supporting
Information) and GC analysis of the later on a chiral stationary
phase gave for both acetates 97:3 er.
[a] 0.10 mmol (aR,R)-5a, 10 mol% Ni(dppp)Cl2, 0.15 mmol of 22, 0.30
mmol salt (mode B). [b] Not determined.
Solvent effect: surprising results were obtained by changing the
solvent from ether to THF. CCR of (aS,S)-5a and (aR,S)-5a with
salt-free ZnPh2 and Ni(dppp)Cl2 in the presence of MgBr2/Et2O
in ether led to a full conversion of the alkenyl sulfoximines and
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10.1002/chem.201901163
Chemistry - A European Journal
10
Scheme 19. CCR of trisubstituted axially chiral alkenyl sulfoximine (aS,S)-Me-
5a with bis(silylmethyl)zinc 22 .
gave the corresponding alkenes (aS)-6a and (aR)-6a in high
yields (Table 1, entries 1 and 2) (Scheme 18). In stark contrast,
experiments conducted under similar conditions but using THF
as solvent saw a low conversion of the substrates and either no
or only minor formation of the alkenes (Table 1, entries 9 and
10). The same solvent dependency was observed in the case of
the CCR with an alkylzinc. While treatment of (aR,R)-5a with
salt-free bis(silylmethy)zinc 22 (3 equiv) in the presence of
MgBr2/Et2O (3 equiv) with Ni(dppp)Cl2 (10 mol%) in ether gave
alkene (aR)-6d in 90% yield (Table 3, entry 1), a similar
experiment in THF resulted in no conversion and the alkenyl
sulfoximine was recovered in 86% yield (Table 3, entry 2). In
both ether and THF the red crystalline Ni(II)-complex was
reduced within short time under formation of a yellow-orange
homogeneous mixture containing the Ni(0)-catalyst.
Interestingly, the CCR with Ni(PPh3)2Cl2 occurred under
inversion of configuration of the chiral axis and gave (aR)-6g in
68:32 er and 32% yield. The er of (aS)-6g was determined by 1H
[37]
NMR spectroscopy in the presence of Agfod/Pr(tfc)3
and the
absolute configuration was assigned based on comparison of its
chirotropic properties with those of alkene (aS)-6d.
(N-sulfonyl)sulfoximines: in a final set of experiments with axially
chiral alkenyl sulfoximines the influence of the substituent at the
N atom of the sulfonimidoyl group upon the CCR was probed by
using the (N-sulfonyl)sulfoximines (aR,S)-5b and (aR,R)-5c.
Alkenyl sulfoximines (aR,S)-5b and (aR,S)-5c were synthesized
through sulfonylation of the corresponding alkenyl (N-
H)sulfoximine (aR)-5d at the
N
atom (see Supporting
Information).
Ph
O
22
Ni dppp
(
o
N T l
SO2
S
e
iM
S
3
l
C
)
2
u
tB
u
tB
r
M B
g
e
er 2
,
H
H
th
-
-
,
a
a
R
°
R 6d
)
5b
)
S
(
(
0 C 4 d
Scheme 20. CCR of alkenyl (N-tosyl)sulfoximine (aR,S)-5b with bis(silyl-
methyl)zinc 22.
CCR of (N-tosyl)sulfoximine (aR,S)-5b with bis(silylmethyl)zinc
22 in the presence of MgBr2/Et2O with Ni(dppp)Cl2 gave the
allylic silane (aR)-6d in 70% yield and 92:8 er (Scheme 20). As
found in the CCR of the alkenyl (N-methyl)sulfoximine (aR,R)-5a,
the presence of the salt was crucial for the CCR of the alkenyl
sulfoximine to occur.
In contrast to alkenyl (N-methyl)sulfoximines, the alkenyl (N-
triflyl)sulfoximine (aR,S)-5c is not metallated by Grignard
reagents at the α-position. This gave reason to study the CCR of
(aR,S)-5c with MeMgI and PhMgBr (Scheme 21). CCR of
(aR,S)-5c with MeMgI (3 equiv) and Ni(PPh3)2Cl2 (8 mol%) in
ether gave alkene (aR)-6b in 84% yield and 98:2 er under
retention of configuration. Under similar conditions the Ni-
catalyzed CCR of (aR,S)-5c with PhMgBr afforded alkene (aR)-
6a in 61% yield and 98:2 er. Remarkably, promotion of CCR by
MgBr2 was not required with both Grignard reagents.
Scheme 18. Ni-Catalyzed CCR of alkenyl sulfoximines in ether and THF.
Ph
O
e
N
SO2C
F
M
H
S
H
e
3
M M I
g
u
tB
u
tB
α-Substituted alkenyl sulfoximine: treatment of the non-terminal
alkenyl sulfoximine (aS,S)-Me-5a (96:4 dr) with salt-free
bis(silylmethyl)zinc 22 (3 equiv) in ether and Ni(dppp)Cl2 (10
mol%) in the absence of MgBr2/Et2O furnished alkene (aS)-6g
in only 40% yield and 79:21 er (Scheme 19). Alkenyl sulfoximine
(aS,S)-Me-5a was recovered in 40% yield and 96:4 dr. CCR in
the presence of MgBr2 afforded (aS)-6g in 55% yield and 61:39
er.
Ni PPh
(
l
3 2C 2
)
°
,
,
e
e
th
r
0 C
5 h
-
-
,
a
c
5
)
a
R
R 6b
S
(
)
(
r
PhM B
g
Ph
H
Ni PPh
l
,
3 2C 2
-
(
)
,
c
5
a
R
u
tB
S
(
)
°
,
e
er
th
5 h
0 C
-
a
a
R 6
(
)
22
e
M
e
M
Ni dppp
(
l
C
)
2
u
tB
Scheme 21. CCR of alkenyl (N-triflyl)sulfoximine (aR,S)-5c with Grignard
reagents.
u
tB
,
e
er
th
e
iM
3
S
e
NM
,
S
r
t 4 d
-
-
-
O
,
a
S
a
e
5
a
6g
)
M
)
S S
(
(
Ph
Acyclic alkenyl sulfoximines
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10.1002/chem.201901163
Chemistry - A European Journal
11
The Ni-catalyzed ACCR of lithioalkenyl sulfoximines (E)-Li-8 with
PhLi primarily affords the phenyl-substituted alkenyllithiums (E)-
Li-9, which suffer a [1,5]-retro-Brook rearrangement. Protonation
of alcoholates (E)-Li-27 furnishes the phenyl- and silyl-
substituted homoallylic alcohols (E)-28 (Scheme 22).[29,45] It was
therefore of interest to see whether a CCR of (E)-8 would also
give access to monosubstituted homoallylic alcohols of type (E)-
9. Gratifyingly, CCR of alkenyl sulfoximine (E)-8a with ZnPh2 (4
equiv) and Ni(dppp)Cl2 (15 mol%) in ether in the presence of
MgBrCl (4 equiv) furnished alkene (E)-9a in 78% yield and ≥98:2
Selective cleavage of the silyl ethers (E)-9b and (E)-9d with
MeCO2H/HCl gave the corresponding alcohols (E)-9e and (E)-9f
in 94% yield and 86% yield, respectively.
Homoallylic alcohols of type (E)-9c and (E)-9d, having an
additional allylic silane moiety, should be interesting synthetic
building blocks.[46]
Ph
iEt
OS
O
22
3
iEt
OS
3
Ni PPh
(
l
3 2C 2
S
)
e
iM
Ph
e
NM
S
Ph
3
r
M B
g
2
r
H
iP
r
,
,
H
iP
e er r
th
t 4 d
-
-
a
E
(
9b
E
8
)
(
)
dr (Scheme 23).
Ph
O
iEt
OS
iEt
OS
3
3
S
LiPh
Ph
iEt
OS
3
R1
R1
e
NM
21
Ni PPh
Ni dppp
(
l
C
)
2
l
3 2C 2
´
R
-
(
)
R2
R2
Li
e
iM
2O
a
8
Ph
S
Li
E
(
)
r
M B
g
-
-
- -
2
r
H
iP
E Li 8
( )
E Li 9
( )
,
,
e
th
er r
t 4 d
-
-
+
c
a
8
E
9
E
(
)
(
)
H
O
Li
O
H+
Ph
iEt
Ph
R1
R1
Ph
iEt
e
OS
O
3
22
Ni PPh
(
iEt
e
OS
3
R2
R2
S
l
3 2C 2
S
3
iEt
3
)
S
r
-
iP
e
iM
3
S
e
r
iP
NM
-
-
28
E
( )
r
M B
g
th
27
E Li
( )
2
H
M
,
,
e
er r
H
M
t 4d
-
-
E
9d
)
(
E
(
8b
)
Scheme 22. Ni-Catalyzed ACCR of acyclic lithioalkenyl sulfoximines (E)-Li-8
with PhLi.
,
H
O
e
M
H H
2O
l
C
CO2
,
THF H
-
e
iM
Ph
S
Interestingly, CCR of the (Z)-configured alkenyl sulfoximine (Z)-
8a[20] was much slower and unselective. After a reaction time of
2 d a mixture of (Z)-8a, (E)-9a and (Z)-9a was isolated in a ratio
3
E
(
9b
)
r
H
e
iP
-
E
9
(
)
of 80:10:10.
Ph
,
e
M
H H
2O
l
CO2
C
O
iEt
H
O
OS
iEt
OS
n
3
3
Z Ph2
,
THF H
S
-
Ni dppp
(
l
2
C
Ph
)
r
E
9d
iP
e
iM
3
e
S
(
)
NM
Ph
iEt
Ph
r
M B
l
C
g
e
H
,
,
M
r
H
r
e
er r
H
iP
iP
th
t 2 d
-
-
-
E
9f
´
a
a
(
)
=
r
8
E
9
E
(
)
(
)
R
iP
n
Z Ph2
Ni dppp
OS
Scheme 24. CCR of acyclic alkenyl sulfoximines (E)-8a and (E)-8b with
bis(silylmethyl)zincs 21 and 22.
3
iEt
OS
3
l
C
)
2
(
H
H
Ph
Ph
-
r
a
9
M B
l
C
+
E
(
g
th
)
,
,
r
iP
e
e
r r
r
t 2 d
iP
Ph
S
e
NM
-
-
O
iE
t
OS
3
iEt
OS
a
H
N H
2O2
a
3
Z 9
( )
Z 8
( )
Ph
a
CO3
e
r
SiM 2OiP
Ph
H
O
Ph
,
THF H
2O
r
H
Scheme 23. CCR of acyclic alkenyl sulfoximines (E)-8a and (Z)-8a with ZnPh2.
r
iP
iP
H
-
-
c
E 9
( )
E 9g
( )
Reaction of (E)-8a with bis(silylmethyl)zincs 22 and 21,
Ni(PPh3)2Cl2 and MgBr2/Et2O afforded the corresponding allylic
silanes (E)-9b and (E)-9c only in 44% yield and 27% yield,
respectively, both in ≥98:2 dr (Scheme 24). The alkenyl
sulfoximine was recovered in 47% yield. In contrast, CCR of
alkenyl sulfoximine (E)-8b with 22, Ni(PPh3)2Cl2 and
MgBr2/Et2O gave the allylic silane (E)-9d in 86% yield and ≥98:2
dr.
H
O
u
B
4NF
-
E 9g
( )
H
O
Ph
THF
r
H
iP
-
h
E 9
( )
Scheme 25. Oxidation of acyclic allylic silane (E)-9c.
The CCR of the acyclic alkenyl sulfoximines were run in the
presence of MgBr2/MgBrCl since without the salt no reaction
occurred.
Oxidation of the allylic silane (E)-9c furnished the mono-
protected allylic diol (E)-9g in 93% yield and ≥98:2 dr (Scheme
25). Homoallylic diols of type (E)-9g are valuable building block
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10.1002/chem.201901163
Chemistry - A European Journal
12
for polyketide synthesis.[47] Cleavage of silyl ether (E)-9g with
fluoride afforded diol (E)-9h in 96% yield.
The Ni-catalyzed reaction of the methylated alkenyl sulfoximine
(aS,S)-Me-5a with ZnPh2 had demonstrated that alkenyl
sulfoximines, carrying a substituent at the α-position, can serve
as substrates in CCR (vide supra). Therefore, the CCR of the
substituted acyclic alkenyl aminosulfoxonium salt (E)-Me-10
(Scheme 28) was investigated. The salt is obtained from alkenyl
sulfoximine (E)-8a in 90% yield in three steps, including lithiation
with MeLi to give lithioalkenyl sulfoximine (E)-Li-8a, followed by
treatment with MeI and methylation of thus obtained alkenyl
sulfoximine (E)-Me-8a with Me3OBF4.[24b] Because of the
absence of a H atom at the α-position of (E)-Me-8a, a Grignard
reagent was used in its CCR. Surprisingly, CCR of the
Alkenyl aminosulfoxonium salts
Methylation of alkenyl sulfoximine (E)-8a with Me3OBF4 gives
the alkenyl aminosulfoxonium salt (E)-10 in nearly quantitative
yield.[24b] Utilization of RMgX or RLi in CCR with alkenyl
aminosulfoxonium salts, which carry a H atom at the α-position,
is not feasible, because of their ready deprotonation under
formation of the corresponding ylides.[21a,24]
Ph
O
iEt
OS
3
iEt
OS
3
n
O
S
Z Ph2
S
Ph
e Ni dppp Cl
Ph
NM
Ph
(
)
2
+
2
aminosulfoxonium
Ni(PPh3)2Cl2 took place with high site-selectivity under
reductive dearylation and gave the alkenyl (N,N-
salt (E)-Me-10
with PhMgBr
and
e
NM
2
r
Ph
r
H
r
H
iP
M B
l
C
g
iP
BF4
,
,
-
-
-
r
THF t 1 d
a
E
( )
9
29
10
S
( )
E
( )
dimethyl)sulfinamide (E)-30 in 94% yield and ≥98:2 dr. It is
assumed that the sulfinamide has the (R)-configuration since
CCR of alkenyl sulfoximines proceeds under retention of
configuration at the S atom. Alkenyl sulfinamides are an
interesting class of compounds, which have thus far received
only scattered attention.[48]
Having obtained this unexpected result, CCR of the parent α-
substituted alkenyl sulfoximine (E)-Me-8a[24b] was studied
(Scheme 29). Treatment of (E)-Me-8a with PhMgBr and
Scheme 26. CCR of alkenyl amino sulfoxonium salt (E)-10 with ZnPh2.
The Ni-catalyzed CCR of salt (E)-10 with ZnPh2/MgBrCl and
Ni(dppp)Cl2 was faster than that of the corresponding alkenyl
sulfoximine (E)-8a and afforded alkene (E)-9a in 85% yield and
≥98:2 dr (Scheme 26). In addition, sulfinamide (R)-29[21a,24] was
formed, which was, however, not isolated.
Ni(PPh3)2Cl2 gave
a
mixture of the alkenyl (N-
Similarly, CCR of salt (E)-10 with bis(silylmethyl)zincs 22 and 21,
Ni(PPh3)2Cl2 and MgBr2/Et2O in THF gave the corresponding
allylic silanes (E)-9b and (E)-9c in 62% yield and 84% yield,
methyl)sulfinamide (E)-31 and alkene (E)-Me-9a, both as single
diastereomers, in a ratio of 77:23. Chromatography afforded the
sulfinamide in 73% yield and ≥98:2 dr. Sulfinamide (E)-31
presumably also has the (R)-configuration. Thus, two competing
CCRs had occurred, reductive dearylation and dealkenylation.
While reductive de-alkylation and dealkenylation of sulfoximines
has frequently been applied in synthesis,[21a,49] reductive
respectively and ≥98:2 dr (Scheme 27).
Ph
O
iEt
3
OS
iEt
OS
3
22
S
Ni PPh
l
3 2C 2
(
)
e
iM
3
e
Ph
NM
S
Ph
2
r
M B
g
2
r
iP
r
H
H
,
,
iP
BF4
r
dearylation has rarely been observed.
O
THF t 4 d
-
-
10
E
( )
t
OSiE 3
E 9b
( )
S
e
Ph
N H M
( )
O
iEt
OS
3
iEt
OS
21
Ni PPh
(
r
e
M
iP
3
r
PhM B
Ni PPh
(
g
-
S
l
3 2C 2
)
E 31
( )
-
10
e
NM
l
3 2C 2
)
e
r
Ph
E
( )
Ph
iM
iP
2O
S
r
,
+
M B
g
2
r
,
.
e
th
er r
r
iP
r
e
M
,
H
t
iP
iEt
OS
THF t 1 5 d
3
-
c
-
-
E 9
( )
Ph
a
8
e
E M
( )
Ph
r
iP
-
e
Scheme 27. CCR of alkenyl amino sulfoxonium salt (E)-10 with
bis(silylmethyl)zins 21 and 22.
M
-
a
9
e
E M
( )
Scheme 29. CCR of the acyclic methyl-substituted alkenyl sulfoximine (E)-Me-
8a with PhMgBr.
CCR of aminosulfoxonium salt (E)-10 with 22 Ni(PPh3)2Cl2 (20
mol%) in THF in the absence of MgBr2 was slow. While
conversion of the salt in the presence of MgBr2 was 95% within
4 d, it was only 50% in the absence of magnesium salt under
Catalytic cycle
similar conditions.
Ph
The Ni-catalyzed CCR of alkenyl (N-methyl)sulfoximines with
organozincs shows the following features: (1) retention of
configuration with Ni(dppp)Cl2 (chelating phosphine) as
precatalyst and alkyl- and arylzincs and requirement of a
promotion by MgBr2, which is efficacious in ether but not in THF,
(2) no requirement of salt promotion in the case of α-substituted
alkenyl sulfoximines, (3) retention of configuration and no
requirement of salt promotion in the case of Ni(PPh3)2Cl2 (non-
chelating phosphine) and ZnPh2, and (4) loss of configurational
integrity in the case of Ni(PPh3)2Cl2 and bis(silylmethyl)zincs.
We assume a Kumada-Corriu-Negishi (KCN) cycle[13] for the Ni-
O
iEt
OS
iEt
OS
3
r
O
S
3
PhM B
g
S
Ni PPh
l
3 2C 2
)
(
e
NM
Ph
Ph
2
e
NM
2
,
r
THF
t
r
e
r
iP
e
M
iP
M
BF4
-
-
-
e
E 30
( )
10
E M
( )
Scheme 28. CCR of acyclic methyl-substituted aminosulfoxonium salt (E)-Me-
10 with PhMgBr.
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10.1002/chem.201901163
Chemistry - A European Journal
13
catalyzed CCR of alkenyl sulfoximines and aminosulfoxonium
salts with organozincs (Scheme 30, only the KCN cycle of
alkenyl sulfoximines is shown). Oxidative addition of the alkenyl
sulfoximine I to the Ni(0)-catalyst affords the alkenyl Ni(II)-
complex II. Subsequent transmetallation of II with an organozinc
yields the alkeny Ni(II)-complex III and sulfinamide (R)-Zn-25.
Finally, reductive elimination of III furnishes alkene IV and the
Ni(0)-catalyst.[50]
[D10]-ether at room temperature revealed strong down-field
shifts of the signals of the α-H atom of the double bond and the
o-H atoms of the phenyl group (Table 5, entries 1−5). A similar
shift variation[53] was observed in CDCl3 as solvent (entries 8
1
and 9). Notably, no shift variation was observed in the H NMR
spectrum of a mixture of (aR,R)-5a and MgBr2/Et2O in [D8]-THF
(entries 6 and 7). Similar but less strong shift variations were
recorded for the alkenyl (N-sulfonyl)sulfoximine (aR,S)-5b in
CDCl3 but none in [D8]-THF (entries 10−13). These
observations demonstrate a coordination of the Lewis basic
sulfonimidoyl group[54] of the alkenyl sulfoximine by MgBr2 in
ether and CDCl3 under formation of (aR,R)-5a-MgBr2 and
(aR,S)-5b-MgBr2. The other salts are expected to form similar
complexes with (aR,R)-5a. While (aR,R)-5a is expected to be
coordinated by MgBr2 at the N atom, (aR,S)-5b is perhaps
coordinated by the salt at the O atoms of the sulfoximine and
sulfonyl group.[28] The lack of a shift variation in THF shows the
absence of a complexation of the sulfonimidoyl group by MgBr2
in this solvent, because THF forms stronger Lewis acid-base
complexes with MgBr2 than ether does.[55] The absence of
nucleofugal complexation of alkenyl sulfoximines in THF
correlates with the experimental observation that MgBr2 fails to
exert a promotion of the CCR in this solvent.
Ph
O
R3
R1
R2
S
H
R1
R2
e
NM
H
I
IV
Ni0L
O
S
Ph
NiII
L
( )
NiII
L
R3
( )
R1
R2
R1
R2
e
NM
H
H
III
II
O
Table 5. 1H NMR spectroscopy of alkenyl sulfoximines in the presence of salts
3
n
Z R
(
)
2
3
(3 equiv) in different solvents at room temperature.a
n
Z R
S
Ph
N
Ph
Ph
O
O
MX
e
M
n
e
NM
S
N
S
-
-
MX
25
R Z
e
M
( )
u
u
tB
tB
H
H
-
-
-
,
,
a
a
a
5
a
5
)
R R
R R
MX
O
S
(
Ph
(
)
O
Ph
M B
r
NiII
L
M B
g
2
S
R1
R2
( )
r
R1
R2
Ph
g
Ph
O
2
N
O
N
o
T l
N
S
H
SO2
e
o
T l
N
M
S
SO2
MX
e
M
H
u
H
-
MX
tB
u
tB
-
r
I
r
2
M B
g
II
M B
g
2
H
-
-
-
,
,
a
R
a
R
5b
5b
MX
S
S
)
(
)
(
r
M B
g
2
entry
alkenyl
MX
-
solvent
δ
δ
δ
O
S
sulfoximine
=CH
6.19
7.37
7.37
7.26
6.76
6.15
6.16
6.20
7.13
6.38
6.62
6.42
6.42
N-Me
2.59
2.81
2.93
2.70
-
o-Ph
3
n
Z R
N
Ph
1
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
[D10]-ether
[D10]-ether
[D10]-ether
[D10]-ether
[D10]-ether
[D8]-THF
[D8]-THF
CDCl3
7.89−7.95
8.33−8.40
8.37−8.48
8.08−8.16
8.02−8.10
7.83−7.90
7.83−7.90
7.88−7.92
8.05−8.15
7.91−7.95
8.02−8.06
7.91−7.95
7.91−7.95
e
M
-
2
MgBr2
MgI2
ZnBr2
LiBr
-
-
-
n
r
2
25
R Z
( )
M B
g
3
Scheme 30. Envisioned cycle of the Ni-catalyzed and MgBr2 promoted CCR
of alkenyl sulfoximines with organozincs (L = dppp).
4
5
Salt promotion: an interesting feature of the CCR of alkenyl
sulfoximines is the general necessity of a promotion by MgBr2,
which is effective in ether but not in THF. The promotion could
be due to a rate enhancement of the oxidative addition[51]
through coordination to the nucleofugal sulfonimidoyl group
under formation of complex I-MgBr2. Rate acceleration of the
Ni(0)-catalyzed CCR by Lewis acids had been previously
observed and generally ascribed to an acceleration of the
oxidative addition through nucleofugal complexation.[13] We had
previously observed a complex formation between allylic (N-
methyl)sulfoximines and BF3.[52] Hence, the behavior of alkenyl
sulfoximine (aR,R)-5a towards various salts was investigated
6
2.54
2.54
2.66
2.68
-
7
MgBr2
-
8
9
MgBr2
-
CDCl3
10
11
12
13
CDCl3
MgBr2
-
CDCl3
-
[D8]-THF
[D8]-THF
-
MgBr2
-
1
1
by H NMR spectroscopy. The H NMR spectra of (aR,R)-5a in
the presence of MgBr2/Et2O, MgI2, ZnBr2 and LiBr (3 equiv) in
[a] Chemical shifts relative to TMS.
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10.1002/chem.201901163
Chemistry - A European Journal
14
The complexation of alkenyl sulfoximines by MgBr2 points to a
promotion of the oxidative addition by the salt. However, the
possibility exists that the transmetallation rather than the
oxidative addition is affected despite the coordination of the
alkenyl sulfoximine by the salt. Reaction of I-MgBr2 with the
Ni(0)-catalyst will generate the alkenyl Ni(II)-complex II-MgBr2,
the sulfonimidoyl group of which is also coordinated by MgBr2.
This complexation could result in a nucleofugal activation and
complexes had been described.[59] A phosphine-dependent loss
of configurational integrity was observed in Pd-catalyzed CCR of
alkenyl halides, which was associated with a (E/Z)-isomerization
of the alkenyl palladium(II)-complexes.[60] In both cases the
mechanism of the isomerization and the precise role played by
the ligand are unknown.
Summary
thus lead to a rate acceleration of the transmetallation.[56]
A
Alkenyl (N-methyl)sulfoximines undergo a dual Ni-catalyzed and
MgBr2 promoted CCR with diaryl- and dialkylzincs, which is with
Ni(dppp)Cl2 as precatalyst generally stereoretentive for both the
C and S atom. The promotion of the CCR of alkenyl sulfoximines
by MgBr2 takes place in ether but not in THF. Complex formation
between alkenyl sulfoximines and MgBr2 in ether may lead to a
nucleofugal activation and an acceleration of the oxidative
addition of the KCN cycle. With Ni(PPh3)2Cl2 as precatalyst the
CCR of axially chiral alkenyl sulfoximines with ZnPh2 requires
no salt promotion, while with bis(silylmethyl)zincs salt promotion
is needed and the configurational integrity of the double bond is
lost. (E)-Configured alkenyl aminosulfoxonium salts also
participate in the Ni-catalyzed CCR with alkyl- and arylzincs in
the presence of MgBr2. They show a higher reactivity than the
corresponding alkenyl sulfoximines.
The Ni-catalyzed CCR of acyclic alkenyl sulfoximines and
aminosulfoxonium salts, carrying a methyl group at the α-
position, with PhMgBr takes a different course und delivers
through reductive dearylation the corresponding alkenyl
sulfinamides under stereoretention at the S atom.
The stereoselective synthesis of axially chiral alkenes and
exocyclic alkenes from the corresponding ketones has been
achieved in two steps, including a diastereoselective IPO with
chiral lithiomethyl sulfoximines and the Ni-catalyzed/salt
promoted CCR of the alkenyl sulfoximines with diorganozincs.
distinction between both modes of acceleration is not possible
on the basis of the data gathered up to now.
Because of the coordination of the alkenyl sulfoximine by MgBr2,
transmetallation of II-MgBr2 leads to the formation of a Zn-
sulfinamide-MgBr2 complex, (R)-Zn-25-MgBr2 (cf. Scheme 30).
This renders the catalytic cycle stoichiometric in MgBr2, a
deduction which correlates with the experimental finding.
Whether salt promotion is required in CCR of the axially chiral
(aS,S)-5a and (aR,S)-5a with ZnPh2 hinges on the phosphine
ligand of the precatalyst. While with chelating bisphosphine
precatalyst Ni(dppp)Cl2 salt promotion is necessary, it is not with
non-chelating monophosphine precatalyst Ni(PPh3)2Cl2. The
origin of this finding remains unexplained. Perhaps dissociation
of PPh3 from the Ni(0)-catalyst derived from Ni(PPh3)2Cl2 plays
a role, giving a more active catalyst.[57]
Zincate formation: although the Lewis acid-base reaction of
alkenyl sulfoximines with MgBr2 strongly points to a promotion of
the oxidative addition or transmetallation, a completely different
mode of promotion of the CCR by the salt has in principle also to
be considered. This is the formation of organozincates from
organozincs and MgBr2 according to equation (1), exhibiting a
higher reactivity in transmetallation than the organozincs.
Several studies have appeared, showing that salts generated in
the metathesis reaction of ZnX2 with RM (M = Li, MgX) engage
in the formation of mixed metal organozincates with the
organozincs, which have a higher reactivity in CCR.[58]
Acknowledgements. We thank Professors Dr. Helmut
Vorbrüggen and Dr. Werner Skuballa for helpful discussions and
the generous gift of chemicals, Professor Dr. Harald Günther for
NMR measurements, and Cornelia Vermeeren for the
SCHAKAL figures and GC analyses. We gratefully acknowledge
support of this work by the analytic and spectroscopic
laboratories of the departments of chemistry of RWTH Aachen
University, University Freiburg and Technical University
Darmstadt. Financial support of this work by the Volkswagen
Foundation and Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
+
n
r
M B
g
2
n r −
R Z B
r +
M B
Z R2
1
( )
g
[
] [
]
2
There is evidence, however, speaking against a decisive role of
organozincates in the CCR of alkenyl sulfoximines. First,
promotion by MgBr2 is effective in ether but not in THF, a
solvent in which formation of magnesium zincates should be
more pronounced, because of the stronger cation solvation.
Keywords: Nickel • Cross coupling • Alkenyl sulfoximines •
Second,
1H
NMR
spectroscopy
of
solutions
of
Catalysis • Salt promotion
bis(silylmethyl)zinc 22 and ZnPh2 with MgBr2/Et2O (1 equiv) in
[D10]-ether at room temperature showed only minor shift
differences and no new signals.
[1]
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[3]
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Chemistry - A European Journal
15
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Chemistry - A European Journal
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10.1002/chem.201901163
Chemistry - A European Journal
17
Entry for the Table of Contents
FULL PAPER
Ph
O
Alkenyl sulfoximines undergo a dual
Ni-catalyzed and MgBr2 promoted
stereoretentive cross-coupling reac-
tion (CCR) with organozincs. Salt
promotion is due to a coordination
and activation of the sulfonimidoyl
group. CCR of alkenyl sulfoximines
together with an inverse Peterson
olefination of the corresponding
ketones with chiral lithiomethyl
Irene Erdelmeier, Gerd Bülow, Chang-
Wan Woo, Jürgen Decker, Gerhard
Raabe, Hans-Joachim Gais*
H
H
H
H
e
NM
S
CH 4OR
)
2
(
.
i
RO
RO
RO
RO
H
H
Page No. – Page No.
H
H
.
i
u
u
tB
tB
Cross-Coupling Reaction of Alkenyl
Sulfoximines and Alkenyl Amino-
sulfoxonium Salts With Organo-
zincs by Dual Nickel Catalysis and
Lewis Acid Promotion
e
NM
Ph
S
O
O
Ph
Ph
t
OSiEt3
OSiE 3
.
S
i
´
e
NM
e
Ph
Ph
SiM 2OR
sulfoximines are key steps of
a
r
r
H
H
iP
iP
stereoselective synthesis of exo-
cyclic and axially chiral alkenes.
.
,
,
,
n
:
r
B
g
e e
r
t
h
Z
R2
i
Ni dppp
l
M
C
)
(
2
2
This article is protected by copyright. All rights reserved.